Benzyloxypyridylcyclopropanecarboxylic acids, pharmaceutical compositions and uses thereof

ABSTRACT

The present invention relates to compounds of general formula I, 
                         
wherein the groups R, R 1 , R 2 , R 3 , m and n are defined herein, which have valuable pharmacological properties, in particular bind to the GPR40 receptor and modulate its activity. The compounds are suitable for treatment and prevention of diseases which can be influenced by this receptor, such as metabolic diseases, in particular diabetes type 2.

FIELD OF THE INVENTION

The present invention relates to novelbenzyloxypyridylcyclopropanecarboxylic acids, that are agonists of theG-protein coupled receptor 40 (GPR40, also known as free fatty acidreceptor FFAR 1), to processes for their preparation, to pharmaceuticalcompositions containing these compounds and to their medical use for theprophylaxis and/or treatment of diseases which can be influenced by themodulation of the function of GPR40. Particularly, the pharmaceuticalcompositions of the invention are suitable for the prophylaxis and/ortherapy of metabolic diseases, such as diabetes, more specifically type2 diabetes mellitus, and conditions associated with the disease,including insulin resistance, obesity, cardiovascular disease anddyslipidemia.

BACKGROUND OF THE INVENTION

Metabolic diseases are diseases caused by an abnormal metabolic processand may either be congenital due to an inherited enzyme abnormality oracquired due to a disease of an endocrine organ or failure of ametabolically important organ such as the liver or the pancreas.

Diabetes mellitus is a disease state or process derived from multiplecausative factors and is defined as a chronic hyperglycemia associatedwith resulting damages to organs and dysfunctions of metabolicprocesses. Depending on its etiology, one differentiates between severalforms of diabetes, which are either due to an absolute (lacking ordecreased insulin secretion) or to a relative lack of insulin. Diabetesmellitus Type I (IDDM, insulin-dependent diabetes mellitus) generallyoccurs in adolescents under 20 years of age. It is assumed to be ofauto-immune etiology, leading to an insulitis with the subsequentdestruction of the beta cells of the islets of Langerhans which areresponsible for the insulin synthesis. In addition, in latent autoimmunediabetes in adults (LADA; Diabetes Care. 8: 1460-1467, 2001) beta cellsare being destroyed due to autoimmune attack. The amount of insulinproduced by the remaining pancreatic islet cells is too low, resultingin elevated blood glucose levels (hyperglycemia). Diabetes mellitus TypeII generally occurs at an older age. It is above all associated with aresistance to insulin in the liver and the skeletal muscles, but alsowith a defect of the islets of Langerhans. High blood glucose levels(and also high blood lipid levels) in turn lead to an impairment of betacell function and to an increase in beta cell apoptosis.

Persistent or inadequately controlled hyperglycemia is associated with awide range of pathologies. Diabetes is a very disabling disease, becausetoday's common antidiabetic drugs do not control blood sugar levels wellenough to completely prevent the occurrence of high and low blood sugarlevels. Out of range blood sugar levels are toxic and cause long-termcomplications for example retinopathy, renopathy, neuropathy andperipheral vascular disease. There is also a host of related conditions,such as obesity, hypertension, stroke, heart disease and hyperlipidemia,for which persons with diabetes are substantially at risk.

Obesity is associated with an increased risk of follow-up diseases suchas cardiovascular diseases, hypertension, diabetes, hyperlipidemia andan increased mortality. Diabetes (insulin resistance) and obesity arepart of the “metabolic syndrome” which is defined as the linkage betweenseveral diseases (also referred to as syndrome X, insulin-resistancesyndrome, or deadly quartet). These often occur in the same patients andare major risk factors for development of diabetes type II andcardiovascular disease. It has been suggested that the control of lipidlevels and glucose levels is required to treat diabetes type II, heartdisease, and other occurrences of metabolic syndrome (see e.g., Diabetes48: 1836-1841, 1999; JAMA 288: 2209-2716, 2002).

The free fatty acid receptor GPR40 (also referred to as either FFAR,FFAR1, or FFA1) is a cell-surface receptor and a member of the genesuperfamily of G-protein coupled receptors, which was first identifiedas a so-called orphan receptor, i.e. a receptor without a known ligand,based on the predicted presence of seven putative transmembrane regionsin the corresponding protein (Sawzdargo et al. (1997) Biochem. Biophys.Res. Commun. 239: 543-547). GPR40 is found to be highly expressed inseveral particular cell types: the pancreatic 3 cells andinsulin-secreting cell lines, as well as in enteroendocrine cells, tastecells, and is reported to be expressed in immune cells, splenocytes, andin the human and monkey brain. Meanwhile, fatty acids of varying chainlengths are thought to represent the endogenous ligands for GPR40,activation of which is linked primarily to the modulation of the Gqfamily of intra-cellular signaling G proteins and concomitant inductionof elevated calcium levels, although activation of Gs- and Gi-proteinsto modulate intracellular levels of cAMP have also been reported. GPR40is activated especially by long-chain FFA, particularly oleate, as wellas the PPAR-gamma agonist rosiglitazone.

It has been recognized that the fatty acids that serve as activators forGPR40 augment the elevated plasma glucose-induced secretion of insulinthrough GPR40 receptors that are expressed in the insulin secretingcells (Itoh et al. (2003) Nature 422: 173-176; Briscoe et al. (2003) J.Biol. Chem. 278: 11303-11311; Kotarsky et al. (2003) Biochem. Biophys.Res. Commun. 301: 406-410). Despite initial controversy, the use ofGPR40 agonist appears to be the appropriate for increasing insulinrelease for the treatment of diabetes (see e.g. Diabetes 2008, 57, 2211;J. Med. Chem. 2007, 50, 2807). Typically, long term diabetes therapyleads to the gradual diminution of islet activity, so that afterextended periods of treatment Type 2 diabetic patients need treatmentwith daily insulin injections instead. GPR40 agonists may have thepotential to restore or preserve islet function, therefore, GPR40agonists may be beneficial also in that that they may delay or preventthe diminution and loss of islet function in a Type 2 diabetic patient.

It is well established that the incretins GLP-1 (glucagon-likepeptide-1) and GIP (glucose-dependent insulinotropic peptide; also knownas gastric inhibitory peptide) stimulate insulin secretion and arerapidly inactivated in vivo by DPP-4. These peptidyl hormones aresecreted by endocrine cells that are located in the epithelium of thesmall intestine. When these endocrine cells sense an increase in theconcentration of glucose in the lumen of the digestive tract, they actas the trigger for incretin release. Incretins are carried through thecirculation to beta cells in the pancreas and cause the beta cells tosecrete more insulin in anticipation of an increase of blood glucoseresulting from the digesting meal. Further studies indicating that theGPR40 modulatory role on the release of incretins from theenteroendocrine cells, including CCK, GLP-1, GIP, PYY, and possiblyothers, suggest that GPR40 modulators may contribute to enhanced insulinrelease from the pancreatic beta cells also indirectly by e.g. asynergistic effect of GLP-1 and possibly GIP on the insulin release, andthe other release incretins may also contribute to an overall beneficialcontribution of GPR40 modulation on metabolic diseases. The indirectcontributions of GPR40 modulation on insulin release through theelevation of plasma levels of incretins may be further augmented by thecoadministration of inhibitors of the enzymes responsible for theincretin degradation, such as inhibitors of DPP-4.

Insulin imbalances lead to conditions such as type II diabetes mellitus,a serious metabolic disease. The modulation of the function of GPR40 inmodulating insulin secretion indicates the therapeutic agents capable ofmodulating GPR40 function could be useful for the treatment of disorderssuch as diabetes and conditions associated with the disease, includinginsulin resistance, obesity, cardiovascular disease and dyslipidemia.

OBJECT OF THE PRESENT INVENTION

The object of the present invention is to provide new compounds,hereinafter described as compounds of formula I, in particular newbenzyloxypyridyl-cyclopropanecarboxylic acids, which are active withregard to the G-protein-coupled receptor GPR40, notably are agonists ofthe G-protein-coupled receptor GPR40.

A further object of the present invention is to provide new compounds,in particular new benzyloxypyridylcyclopropanecarboxylic acids, whichhave an activating effect on the G-protein-coupled receptor GPR40 invitro and/or in vivo and possess suitable pharmacological andpharmacokinetic properties to use them as medicaments.

A further object of the present invention is to provide effective GPR40agonists, in particular for the treatment of metabolic disorders, forexample diabetes, dyslipidemia and/or obesity.

A further object of the present invention is to provide methods fortreating a disease or condition mediated by the activation theG-protein-coupled receptor GPR40 in a patient.

A further object of the present invention is to provide a pharmaceuticalcomposition comprising at least one compound according to the invention.

A further object of the present invention is to provide a combination ofat least one compound according to the invention with one or moreadditional therapeutic agents.

Further objects of the present invention become apparent to the oneskilled in the art by the description hereinbefore and in the followingand by the examples.

GPR40 modulators are known in the art, for example, the compoundsdisclosed in WO 2004/041266 (EP 1 559 422), WO 2007/033002, WO2009/157418, and WO 2013/178575. Thebenzyloxypyridylcyclopropanecarboxylic acids of the present inventionmay provide several advantages, such as enhanced potency, high metabolicand/or chemical stability, high selectivity and tolerability, enhancedsolubility, and the possibility to form stable salts.

SUMMARY OF THE INVENTION

In a first aspect, the invention relates to a compound of formula

wherein

-   R is selected from the group R-G1 consisting of    -   H, F, Cl, Br, I, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        C₃₋₆-cycloalkyl, NC—, HNR^(N)—C(═O)—, C₁₋₄-alkyl-NR^(N)—C(═O)—,        C₃₋₆-cycloalkyl-NR^(N)—C(═O)—, heterocyclyl-NR^(N)—C(═O)—,        heteroaryl-NR^(N)—C(═O)—, HOOC—, C₁₋₄-alkyl-O—C(═O)—, O₂N—,        HR^(N)N—, C₁₋₄-alkyl-R^(N)N—, C₁₋₄-alkyl-C(═O)NR^(N)—,        C₃₋₆-cycloalkyl-C(═O)NR^(N)—, heterocyclyl-C(═O)NR^(N)—,        heteroaryl-C(═O)NR^(N)—, C₁₋₄-alkyl-S(═O)₂NR^(N)—,        C₃₋₆-cycloalkyl-S(═O)₂NR^(N)—, heterocyclyl-S(═O)₂NR^(N)—,        heteroaryl-S(═O)₂NR^(N)—, HO—, C₁₋₆-alkyl-O—,        HOOC—C₁₋₃-alkyl-O—, C₃₋₆-cycloalkyl-C₁₋₃-alkyl-O—,        heterocyclyl-C₁₋₃-alkyl-O—, phenyl-C₁₋₃-alkyl-O—,        C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, heteroaryl-O—,        C₁₋₄-alkyl-S—, C₃₋₆-cycloalkyl-S—, heterocyclyl-S—,        C₁₋₄-alkyl-S(═O)—, C₃₋₆-cycloalkyl-S(═O)—, heterocyclyl-S(═O)—,        C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-S(═O)₂—,        heterocyclyl-S(═O)₂—, phenyl-S(═O)₂—, heteroaryl-S(═O)₂—,        HNR^(N)—S(═O)₂—, C₁₋₄-alkyl-NR^(N)—S(═O)₂—, heterocyclyl,        phenyl, and heteroaryl,    -   wherein each alkyl, cycloalkyl, and heterocyclyl group or        sub-group within the groups forming R is optionally substituted        with 1 or more F atoms and optionally substituted with 1 to 3        groups independently selected from Cl, C₁₋₃-alkyl, NC—,        (R^(N))₂N—, HO—, C₁₋₃-alkyl-O—, and C₁₋₃-alkyl-S(═O)₂—; and    -   wherein each phenyl and heteroaryl group or sub-group within the        groups forming R is optionally substituted with 1 to 5        substituents independently selected from F, Cl, C₁₋₃-alkyl,        HF₂C—, F₃C—, NC—, (R^(N))₂N—, HO—, C₁₋₃-alkyl-O—, F₃C—O—, and        C₁₋₃-alkyl-S(═O)₂—;    -   wherein each heterocyclyl group or sub-group within the groups        forming R is selected from        -   a cyclobutyl group wherein 1 CH₂ group is replaced by            —NR^(N)— or —O—;        -   a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced by            —C(═O)—, —NR^(N)—, —O—, —S— or —S(═O)₂— and/or 1 CH group is            replaced by N;        -   a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced by            —NR^(N)— or —O—, a second CH₂ group is replaced by —NR^(N)—,            —C(═O)— or —S(═O)₂— and/or 1 CH group is replaced by N; and        -   a C₅₋₆-cycloalkyl group wherein 2 CH₂ groups are replaced by            —NR^(N)— or 1 CH₂ group by —NR^(N)— and the other by —O— and            a third CH₂ group is replaced by —C(═O)— or —S(═O)₂— and/or            1 CH group is replaced by N;    -   wherein each heteroaryl group or sub-group within the groups        forming R is selected from        -   tetrazolyl and a 5- or 6-membered heteroaromatic ring which            contains 1, 2, or 3 heteroatoms independently of each other            selected from ═N—, —NR^(N)—, —O—, and —S—, wherein in            heteroaromatic groups containing a —HC═N— unit this group is            optionally replaced by —NR^(N)—C(═O)—;    -   wherein in heteroaryl and heterocyclyl rings with one or more NH        groups, each of said NH groups is replaced by NR^(N);-   R¹ is selected from the group R¹-G1 consisting of H, F, Cl,    C₁₋₄-alkyl, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkyl,    C₁₋₄-alkyl-O—C₁₋₄-alkyl, NC—, HO—, C₁₋₄-alkyl-O—,    C₃₋₆-cycloalkyl-O—, C₁₋₄-alkyl-S—, C₁₋₄-alkyl-S(O)—, and    C₁₋₄-alkyl-S(O)₂—,    -   wherein any alkyl and cycloalkyl group or sub-group within the        groups forming R¹ is optionally substituted with 1 or more F        atoms, and wherein multiple R¹ may be identical or different if        m is 2, 3 or 4;-   m is an integer selected from 1, 2, 3, and 4;-   R² is selected from the group R²-G1 consisting of H, F, Cl,    C₁₋₄-alkyl, NC—, and C₁₋₄-alkyloxy,    -   wherein any alkyl group or sub-group within the groups forming        R² is optionally substituted with 1 or more F atoms, and wherein        multiple R² may be identical or different if n is 2 or 3;-   R³ is selected from the group R³-G1 consisting of H, F, Cl,    C₁₋₄-alkyl, NC—, and C₁₋₄-alkyl-O—,    -   wherein each alkyl group or sub-group within the groups forming        R³ is optionally substituted with 1 or more F atoms;-   n is an integer selected from 1, 2, and 3;-   R^(N) is independently of each other selected from the group    R^(N)-G1 consisting of H, C₁₋₄-alkyl, HO—C₁₋₄-alkyl-(H₂C)—,    C₁₋₃-alkyl-O—C₁₋₄-alkyl-, C₁₋₄-alkyl-C(═O)—, C₁₋₄-alkyl-NH—C(═O)—,    C₁₋₄-alkyl-N(C₁₋₄-alkyl)-C(═O)—, C₁₋₄-alkyl-O—C(═O)—, and    C₁₋₄-alkyl-S(═O)₂—,    -   wherein each alkyl group or sub-group within the groups forming        R^(N) is optionally substituted with 1 or more F atoms;        wherein in any definition mentioned hereinbefore and if not        specified otherwise, any alkyl group or sub-group may be        straight-chained or branched,        the isoforms, tautomers, stereoisomers, metabolites, prodrugs,        solvates, hydrates, and the salts thereof, particularly the        physiologically acceptable salts thereof with inorganic or        organic acids or bases, or the combinations thereof.

The extension-Gn used within the definitions is meant to identify genusn of the respective substituent. For example, R-G1 defines genus 1 ofthe substituent R.

The expression “optionally substituted with 1 or more F atoms” meansthat none or one up to successively all H atoms bound to carbon atoms ofthe respective group or submoiety may be replaced by F atoms, preferably1 to 5H atoms or, more preferred, 1 to 3H atoms may be replaced by Fatoms.

In a further aspect this invention relates to a pharmaceuticalcomposition, comprising one or more compounds of general formula I orone or more pharmaceutically acceptable salts thereof according to theinvention, optionally together with one or more inert carriers and/ordiluents.

In a further aspect this invention relates to a method for treatingdiseases or conditions which are mediated by activating theG-protein-coupled receptor GPR40 in a patient in need thereofcharacterized in that a compound of general formula I or apharmaceutically acceptable salt thereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a metabolic disease or disorder, such as diabetes,dyslipidemia and/or obesity, in a patient in need thereof characterizedin that a therapeutically effective amount of a compound of generalformula I or a pharmaceutically acceptable salt thereof is administeredto the patient.

According to another aspect of the invention, there is provided the useof a compound of the general formula I or a pharmaceutically acceptablesalt thereof for the manufacture of a medicament for a therapeuticmethod as described hereinbefore and hereinafter.

According to another aspect of the invention, there is provided acompound of the general formula I or a pharmaceutically acceptable saltthereof for use in a therapeutic method as described hereinbefore andhereinafter.

In a further aspect this invention relates to a method for treating adisease or condition mediated by the activation of the G-protein-coupledreceptor GPR40 in a patient that includes the step of administering tothe patient in need of such treatment a therapeutically effective amountof a compound of the general formula I or a pharmaceutically acceptablesalt thereof in combination with a therapeutically effective amount ofone or more additional therapeutic agents.

In a further aspect this invention relates to the use of a compound ofthe general formula I or a pharmaceutically acceptable salt thereof incombination with one or more additional therapeutic agents for thetreatment of diseases or conditions which are mediated by the activationof the G-protein-coupled receptor GPR40.

In a further aspect this invention relates to a pharmaceuticalcomposition which comprises a compound according to general formula I ora pharmaceutically acceptable salt thereof and one or more additionaltherapeutic agents, optionally together with one or more inert carriersand/or diluents.

Other aspects of the invention become apparent to the one skilled in theart from the specification and the experimental part as describedhereinbefore and hereinafter.

DETAILED DESCRIPTION

Unless otherwise stated, the groups, residues, and substituents,particularly R, R¹, R², R³, m and n are defined as above andhereinafter. If residues, substituents, or groups occur several times ina compound, they may have the same or different meanings. Some preferredmeanings of individual groups and substituents of the compoundsaccording to the invention will be given hereinafter. Any and each ofthese definitions may be combined with each other.

R:

R-G1:

The group R is preferably selected from the group R-G1 as definedhereinbefore.

R-G2:

In another embodiment the group R is selected from the group R-G2consisting of H, F, Cl, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NC—,HNR^(N)—C(═O)—, C₁₋₄-alkyl-NR^(N)—C(═O)—, C₃₋₆-cycloalkyl-NR^(N)—C(═O)—,heterocyclyl-NR^(N)—C(═O)—, HOOC—, HR^(N)N—, C₁₋₄-alkyl-R^(N)N—,C₁₋₄-alkyl-C(═O)NR^(N)—, C₃₋₆-cycloalkyl-C(═O)NR^(N)—,heterocyclyl-C(═O)NR^(N)—, C₁₋₄-alkyl-S(═O)₂NR^(N)—, HO—, C₁₋₆-alkyl-O—,HOOC—(C₁₋₂-alkyl)-O—, cyclopropyl-H₂C—O—, heterocyclyl-C₁₋₂-alkyl-O—,phenyl-C₁₋₂-alkyl-O—, C₃₋₆-cycloalkyl-O—, heterocyclyl-O—,heteroaryl-O—, C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-S(═O)₂—,heterocyclyl-S(═O)₂—, HNR^(N)—S(═O)₂—, C₁₋₄-alkyl-NR^(N)—S(═O)₂—,heterocyclyl, and heteroaryl,

-   -   wherein each alkyl, cycloalkyl, and heterocyclyl group or        sub-group within the groups forming R is optionally substituted        with 1 or more F atoms and optionally substituted with 1 to 2        groups independently selected from Cl, H₃C—, NC—, R^(N)HN—, HO—,        H₃C—O—, and H₃C—S(═O)₂—;    -   wherein each heteroaryl group or sub-group within the groups        forming R is optionally substituted with 1 to 3 substituents        independently selected from F, Cl, H₃C—, F₃C—, NC—, (R^(N))₂N—,        HO—, H₃C—O—, F₃C—O—, and H₃C—S(═O)₂—;    -   wherein each heterocyclyl group or sub-group within the groups        forming R is selected from        -   a cyclobutyl group wherein 1 CH₂ group is replaced by            —NR^(N)— or —O—;        -   a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced by            —C(═O)—, —NR^(N)—, —O—, —S— or —S(═O)₂— and/or 1 CH group is            replaced by N;        -   a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced by            —NR^(N)— or —O—, a second CH₂ group is replaced by —NR^(N)—,            —C(═O)— or —S(═O)₂— and/or 1 CH group is replaced by N;    -   wherein each heteroaryl group or sub-group within the groups        forming R is selected from        -   tetrazolyl, a 5-membered heteroaromatic ring which contains            1, 2 or 3 heteroatoms independently of each other selected            from ═N—, —NH—, O and S, and a 6-membered heteroaromatic            ring which contains 1 or 2 ═N— atoms, wherein a —HC═N— unit            is optionally replaced by —NH—C(═O)—;    -   and wherein in each of the above heteroaryl and heterocyclyl        group or sub-group containing one or more NH, said NH group(s)        is/are replaced by NR^(N).        R-G3:

In another embodiment the group R is selected from the group R-G3consisting of H, F, Cl, C₁₋₄-alkyl, NC—, H₂N—C(═O)—,C₁₋₃-alkyl-NR^(N)—C(═O)—, HOOC—, H₂N—, C₁₋₃-alkyl-C(═O)NR^(N)—,C₁₋₄-alkyl-S(═O)₂NR^(N)—, HO—, C₁₋₅-alkyl-O—, HOOC—CH₂—O—,cyclopropyl-H₂C—O—, heterocyclyl-CH₂—O—, phenyl-CH₂—O—,C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, heteroaryl-O—,heterocyclyl-S(═O)₂—, heterocyclyl, and heteroaryl,

-   wherein each alkyl, cycloalkyl, and heterocyclyl group or sub-group    within the groups forming R is optionally substituted with 1 or more    F atoms and optionally substituted with 1 group selected from Cl,    H₃C—, NC—, R^(N)HN—, HO—, H₃C—O—, and H₃C—S(═O)₂—;-   wherein each heteroaryl group or sub-group within the groups forming    R is optionally substituted with 1 to 2 substituents independently    selected from F, Cl, H₃C—, F₃C—, NC—, (R^(N))₂N—, HO—, H₃C—O—,    F₃C—O—, and H₃C—S(═O)₂—;-   wherein each heterocyclyl or sub-group within the groups forming R    is selected from a cyclobutyl group wherein 1 CH₂ group is replaced    by —NR^(N)— or —O—; a C₅₋₆-cycloalkyl group wherein 1 CH₂ group is    replaced by —C(═O)—, —NR^(N)—, —O—, —S— or —S(═O)₂— and/or 1 CH    group is replaced by N;-   wherein each heteroaryl group or sub-group within the groups forming    R is selected from tetrazolyl, a 5-membered heteroaromatic ring    which contains 1, 2 or 3 heteroatoms independently of each other    selected from ═N—, —NH—, O and S, and a 6-membered heteroaromatic    ring which contains 1 or 2 ═N— atoms, wherein a —HC═N— unit is    optionally replaced by —NH—C(═O)—;-   and wherein in each heteroaryl and heterocyclyl group or sub-group    mentioned for R-G3 containing one or more NH, said NH group(s)    is/are replaced by NR^(N).    R-G4:

According to another embodiment the group R is selected from the groupR-G4 consisting of:

-   H, C₁₋₃-alkyl, Cl, (H₃C)₂N—C(═O)—, HOOC—;-   H₃C—O— optionally monosubstituted with C₁₋₄-alkyl, oxetanyl,    tetrahydrofuranyl, or tetrahydropyranyl,    -   wherein the C₁₋₄-alkyl group optionally attached to H₃C—O— is        optionally monosubstituted with HO— or H₃C—S(═O)₂—, and    -   wherein said oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl        groups are optionally monosubstituted with H₃C—;-   tetrahydrofuranyl-O— and tetrahydropyranyl-O—; and-   a heteroaryl group selected from pyrazolyl, tetrazolyl, pyridyl,    pyridin-2-onyl, pyridazinyl, pyrazinyl, and pyrimidinyl,    -   wherein each of said heteroaryl groups is optionally        monosubstituted with H₃C— or H₃C—O—, and    -   wherein each H—N group in said heteroaryl groups is optionally        replaced with H₃C—N or (H₃C)₂C(OH)—H₂C—N.        R-G5:

In another embodiment the group R is selected from the group R-G5consisting of H, Cl, H₃C—H₂C—, (H₃C)₂N—C(═O)—, HOOC—, H₃C—O—,

-   wherein the asterisk (-*) indicates the site/point of attachment.    R¹:    R¹-G1:

The group R¹ is preferably selected from the group R¹-G1 as definedhereinbefore.

R¹-G2:

According to one embodiment the group R¹ is selected from the groupR¹-G2 consisting of H, F, Cl, C₁₋₃-alkyl, cyclopropyl, NC—, HO—, andC₁₋₃-alkyl-O—,

-   -   wherein each alkyl group or sub-group within the groups        mentioned under R¹-G2 is optionally substituted with 1 or more F        atoms.        R¹-G3:

According to one embodiment the group R¹ is selected from the groupR¹-G3 consisting of H, F, Cl, H₃C—, H₃C—H₂C—, (H₃C)₂HC—, F₃C—, NC—, andH₃C—O—.

R¹-G4:

According to one embodiment the group R¹ is selected from the groupR¹-G4 consisting of H and H₃C—.

R²:

R²-G1:

The group R² is preferably selected from the group R²-G1 as definedhereinbefore.

R²-G2:

In another embodiment the group R² is selected from the group R²-G2consisting of H, F, Cl, H₃C—, F₃C—, NC—, and H₃CO—.

R²-G3:

In another embodiment the group R² is selected from the group R²-G3consisting of H, F, and F₃C—.

R²-G4:

In another embodiment the group R² is selected from the group R²-G4consisting of H.

R²-G5:

In another embodiment the group R² is selected from the group R²-G5consisting of F.

R²-G6:

In another embodiment the group R² is selected from the group R²-G5consisting of F₃C—.

R³:

R³-G1:

The group R³ is preferably selected from the group R³-G1 as definedhereinbefore.

R³-G2:

In another embodiment the group R³ is selected from the group R³-G2consisting of of H, F, Cl, H₃C—, NC—, and H₃CO—.

R³-G3:

In another embodiment the group R³ is selected from the group R³-G3consisting of H.

R^(N):

R^(N)-G1:

The group R^(N) is preferably selected from the group R^(N)-G1 asdefined hereinbefore.

R^(N)-G2:

In another embodiment the group R^(N) is selected from the groupR^(N)-G2 consisting of H, C₁₋₃-alkyl, HO—C₁₋₄-alkyl-H₂C—,H₃C—O—C₁₋₄-alkyl-, C₁₋₃-alkyl-C(═O)—, and C₁₋₃-alkyl-S(═O)₂—.

R^(N)-G3:

In another embodiment the group R^(N) is selected from the groupR^(N)-G3 consisting of H, H₃C—, HO—C₃-alkyl-H₂C—, H₃C—C(═O)—, andH₃C—S(═O)₂—.

m:

m is an integer selected from 1, 2, 3 and 4.

Preferably, m is an integer selected from 1 and 2.

More preferably, m is 2.

n:

n is an integer selected from 1, 2 and 3.

Preferably, n is an integer selected from 1 and 2.

More preferably, n is 1.

The following preferred embodiments of compounds of the formula I aredescribed using generic formulae I.1, I.2, I.3, I.4, I.5, and I.6,wherein any tautomers, solvates, hydrates and salts thereof, inparticular the pharmaceutically acceptable salts thereof, areencompassed.

Examples of preferred subgeneric embodiments (E) according to thepresent invention are set forth in the following Table 1, wherein eachsubstituent group of each embodiment is defined according to thedefinitions set forth hereinbefore and wherein all other substituents ofthe formulae I, I.1, I.2, I.3, I.4, I.5, and I.6 are defined accordingto the definitions set forth hereinbefore. For example, the entry-G1 inthe column under R— and in the line of E1 means that in embodiment E1substituent R is selected from the definition designated R-G1. The sameapplies analogously to the other variables incorporated in the generalformulae.

TABLE 1 E R- R¹- R²- R³- R^(N)- m n E -G1 -G1 -G1 -G1 -G1 1,2,3,4 1,2,3E2 -G1 -G1 -G1 -G2 -G2 1,2 1,2 E3 -G1 -G1 -G1 -G3 -G3 1,2 1,2 E4 -G1 -G1-G2 -G3 -G3 1,2 1,2 E5 -G1 -G2 -G2 -G3 -G1 1,2 1,2 E6 -G1 -G2 -G2 -G2-G2 1,2 1,2 E7 -G1 -G2 -G2 -G3 -G3 1,2 1,2 E8 -G2 -G1 -G1 -G1 -G1 1,21,2 E9 -G3 -G1 -G1 -G1 -G1 1,2 1,2 E10 -G3 -G1 -G2 -G2 -G2 1,2 1,2 E11-G3 -G2 -G2 -G2 -G2 1,2 1,2 E12 -G2 -G2 -G2 -G3 -G3 1,2 1,2 E13 -G3 -G2-G2 -G3 -G3 1,2 1,2 E14 -G1 -G3 -G2 -G3 -G3 1,2 1,2 E15 -G1 -G2 -G3 -G3-G3 1,2 1,2 E16 -G1 -G3 -G3 -G3 -G3 1,2 1,2 E17 -G1 -G4 -G3 -G3 -G3 1,21,2 E18 -G2 -G3 -G2 -G3 -G3 1,2 1,2 E19 -G2 -G2 -G3 -G3 -G3 1,2 1,2 E20-G2 -G3 -G3 -G3 -G3 1,2 1,2 E21 -G2 -G4 -G3 -G3 -G3 1,2 1,2 E22 -G3 -G3-G2 -G3 -G3 1,2 1,2 E23 -G3 -G2 -G3 -G3 -G3 1,2 1,2 E24 -G3 -G3 -G3 -G3-G3 1,2 1,2 E25 -G3 -G4 -G3 -G3 -G3 1,2 1,2 E26 -G4 -G3 -G2 -G3 — 2 1,2E27 -G4 -G2 -G3 -G3 — 2 1,2 E28 -G4 -G3 -G3 -G3 — 2 1,2 E29 -G4 -G4 -G3-G3 — 2 1,2 E30 -G5 -G3 -G2 -G3 — 2 1,2 E31 -G5 -G2 -G3 -G3 — 2 1,2 E32-G5 -G3 -G3 -G3 — 2 1,2 E33 -G5 -G4 -G3 -G3 — 2 1,2

Another embodiment concerns those compounds of formula I, wherein

R is selected from the group consisting of

H, C₁₋₃-alkyl, Cl, (H₃C)₂N—C(═O)—, HOOC—;

H₃C—O— optionally monosubstituted with C₁₋₄-alkyl, oxetanyl,tetrahydrofuranyl, or tetrahydropyranyl,

-   -   wherein the C₁₋₄-alkyl group optionally attached to H₃C—O— is        optionally monosubstituted with HO— or H₃C—S(═O)₂—, and    -   wherein said oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl        groups are optionally monosubstituted with H₃C—;        tetrahydrofuranyl-O— and tetrahydropyranyl-O—; and        a heteroaryl group selected from pyrazolyl, tetrazolyl, pyridyl,        pyridin-2-onyl, pyridazinyl, pyrazinyl, and pyrimidinyl,    -   wherein each of said heteroaryl groups is optionally        monosubstituted with H₃C— or H₃C—O—, and    -   wherein each H—N group in said heteroaryl groups is optionally        replaced with H₃C—N or (H₃C)₂C(OH)—H₂C—N;        R¹ is selected from the group consisting of H, F, Cl, H₃C—,        H₃C—H₂C—, (H₃C)₂HC—, F₃C—, NC—, and H₃C—O—;        m is 2;        R² is H, F, or F₃C—;        n is 1 or 2; and        R³ is H.

Another embodiment concerns those compounds of formula I, wherein

R is selected from the group consisting of H, Cl, H₃C—H₂C—,(H₃C)₂N—C(═O)—, HOOC—, H₃C—O—,

wherein the asterisk (-*) indicates the site/point of attachment;R¹ is H or H₃C—;m is 2;R² is H, F, or F₃C—;n is 1 or 2; andR³ is H.

Particularly preferred compounds, including their tautomers andstereoisomers, the salts thereof, or any solvates or hydrates thereof,are described in the experimental section hereinafter.

The compounds according to the invention and their intermediates may beobtained using methods of synthesis which are known to the one skilledin the art and described in the literature of organic synthesis forexample using methods described in “Comprehensive OrganicTransformations”, 2^(nd) Edition, Richard C. Larock, John Wiley & Sons,2010, and “March's Advanced Organic Chemistry”, 7^(th) Edition, MichaelB. Smith, John Wiley & Sons, 2013. Preferably, the compounds areobtained analogously to the methods of preparation explained more fullyhereinafter, in particular as described in the experimental section. Insome cases the sequence adopted in carrying out the reaction schemes maybe varied. Variants of these reactions that are known to the skilled manbut are not described in detail here may also be used. The generalprocesses for preparing the compounds according to the invention willbecome apparent to the skilled man on studying the schemes that follow.Starting compounds are commercially available or may be prepared bymethods that are described in the literature or herein, or may beprepared in an analogous or similar manner. Before the reaction iscarried out any corresponding functional groups in the compounds may beprotected using conventional protecting groups. These protecting groupsmay be cleaved again at a suitable stage within the reaction sequenceusing methods familiar to the skilled man and described in theliterature for example in “Protecting Groups”, 3^(rd) Edition, Philip J.Kocienski, Thieme, 2005, and “Protective Groups in Organic Synthesis”,4^(th) Edition, Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons,2006.

The compounds of the invention I are preferably accessed from aprecursor II that bears the carboxylic acid function in a protected ormasked form as sketched in Scheme 1; R, R¹, R², R³, m and n have themeanings as defined hereinbefore and hereinafter. Suited precursorgroups for the carboxylic acid may be, e.g., a carboxylic ester, acarboxylic amide, cyano, an olefin, an oxazole, or a thiazole. All thesegroups have been transformed into the carboxylic acid function bydifferent means which are described in the organic chemistry literatureand are known to the one skilled in the art. The preferred precursorgroup is a C₁₋₄-alkyl or benzyl carboxylate, each of which may beadditionally mono- or polysubstituted with fluorine, methyl, and/ormethoxy. These ester groups may be hydrolyzed with an acid, such ashydrochloric acid or sulfuric acid, or an alkali metal hydroxide, suchas lithium hydroxide, sodium hydroxide, or potassium hydroxide, to yieldthe carboxylic acid function; the hydrolysis is preferably conducted inaqueous solvents, such as water and tetrahydrofuran, 1,4-dioxane,alcohol, e.g., methanol, ethanol, and isopropanol, or dimethylsulfoxide, at 0 to 120° C. A tert-butyl ester is preferably cleavedunder acidic conditions with, e.g., trifluoroacetic acid or hydrochloricacid, in a solvent such as dichloromethane, 1,4-dioxane, isopropanol, orethyl acetate. A benzyl ester is advantageously cleaved using hydrogenin the presence of a transition metal, preferably palladium on carbon.Benzyl esters bearing electron donating groups, such as methoxy, on thearomatic ring may also be removed under oxidative conditions; cericammonium nitrate (CAN) or 2,3-dichloro-5,6-dicyanoquinone (DDQ) are twocommonly used reagents for this approach. The carboxylic acid group mayalso be introduced at an earlier stage of the synthesis, e.g., prior tothe C—C coupling of the two phenyl subgroups as described in theexperimental section.

Compounds of general structure II may be accessed as described in theexperimental section and depicted in Scheme 2. Starting form pyridineIII compound IV is obtained via a transition metal catalyzed borylationwith a diboron reagent, such as bis(pinacolato)diboron, using atransition metal catalyst precursor, such as Pd(PPh₃)₄ or PdCl₂(dppf),and a base, such as potassium acetate, in dimethylsulfoxide or1,4-dioxane at 60 to 100° C. Compound IV is then oxidized with hydrogenperoxide in the presence of a base, e.g., sodium hydroxide, or an acid,e.g., acetic acid, to give hydroxypyridine V. Hydroxypyridine V may bealkylated with a benzyl halide or pseudohalide VI (Y═Cl, Br, OSO₂Me),that bears an additional group (X═Cl, Br, I, B(OH)₂, B(OCMe₂CMe₂O)) onthe phenyl ring for further derivatization, using a base, e.g., K₂CO₃ orNaH, in a solvent, e.g., N,N-dimethylformamide or tetrahydrofuran, at 20to 100° C. to give compound VII. Alternatively, compound VII is obtainedfrom the corresponding benzylalcohol VI (Y═OH) and hydroxypyridine Vemploying the conditions of the Mitsunobu reaction, triphenylphosphineand diisopropyl azodicarboxylate in tetrahydrofuran or toluene. Couplingof pyridines VII with benzenes VIII is achieved by applying theconditions of the Suzuki-Miyaura coupling reaction to give compoundsII′. Accordingly, pyridines VII are employed as boronic acids or estersand benzenes VIII as chlorides, bromides, or iodides in the presence ofa Pd catalyst precursor, e.g.,bis[di-tert-butyl-(4-dimethylaminophenyl)-phosphine]dichloro-palladium(II),in 1,4-dioxane or N,N-dimethylformamide at 60 to 110° C. The reactivityof the two coupling partners VII and VIII may be reversed, i.e. compoundVII is employed as the electrophilic (X═Cl, Br, I) and compound VIII asthe nucleophilic partner (Z═B(OH)₂, B(OCMe₂CMe₂O)), to provide compoundsII′ under analogous reaction conditions.

Compounds of general structure III wherein R³ has the meaning as definedhereinbefore and hereinafter and CP is a suitable carboxylic acid estergroup can be synthesized as summarized in Scheme 3.

Acrylic acid ester IX is reacted with a methylene synthetic equivalentto give ester III′. Suitable reagents for this transformation includediazomethane in the presence of a transition metal catalyst such aspalladium diacetate (see, e.g., WO2011/94890), trimethyloxosulfoniumhalide in the presence of a base such as sodium hydride (see, e.g.,WO2005/103032), and diiodomethane in the presence of copper and zinc(see, e.g., U.S. Pat. No. 628,476). Generally, use of a trans-acrylicacid ester in these reactions leads to predominant formation of atrans-substituted cyclopropyl ester. Enantioselective variants of thistype of reaction are reported in the literature such as the one usingdiazomethane and chiral copper complexes (see, e.g., TetrahedronAsymmetry 2003, 14, 867-872).

Pyridine III′ is also obtained from vinylpyridine X and diazoaceticester XI in the presence of a transition metal catalyst. Suitablecatalyst systems for this transformation include, for example, palladiumdiacetate (see, e.g., WO2007/104717), cobalt(II) porphyrins (see, e.g.,WO2006/103503), rhodium complexes (see, e.g., WO2006/87169), and coppercomplexes (see, e.g., WO2010/51819). Mixtures of cis- andtrans-cyclopropyl esters are generally formed with the trans-systempredominant and the ratio depending on the catalyst system andsubstrates used. Enantioselective reactions of this type are reportedusing chiral transition metal catalysts derived from copper and cobalt(see, e.g., J. Am. Chem Soc. 1991, 113, 726-728) and variations thereof.

Another proceeding to access compound III′ employs epoxide XII andphosphonoacetate XIII. The reaction is commonly carried out in thepresence of a base such as an alcoholate, e.g., NaOEt, NaOtBu, NaOtPent,KOtBu, and KOtPent, LiN(iPr)₂, LiN(SiMe₃)₂, NaH, or nBuLi, in a solventsuch as hexane, benzene, toluene, tetrahydrofuran, 1,2-dimethoxyethane,1,4-dioxane, dimethylsulfoxide, or mixtures thereof, at 0 to 160° C. Theepoxide XII is accessed using standard procedures in organic synthesissuch as epoxidation of the corresponding alkene (X), base inducedcyclization of the corresponding chloro- or bromohydrin derivative, orCorey-Chaykovsky reaction of the corresponding pyridinecarbaldehyde andan appropriate sulfur ylide.

The synthetic routes presented may rely on the use of protecting groups.For example, potentially reactive groups present, such as hydroxy,carbonyl, carboxy, amino, alkylamino, or imino, may be protected duringthe reaction by conventional protecting groups which are cleaved againafter the reaction. Suitable protecting groups for the respectivefunctionalities and their removal are well known to the one skilled inthe art and are described in the literature of organic synthesis forexample in “Protecting Groups”, 3^(rd) Edition, Philip J. Kocienski,Thieme, 2005, or “Protective Groups in Organic Synthesis”, 4^(th)Edition, Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons, 2006.

The compounds of general formula I may be resolved into theirenantiomers and/or diastereomers as mentioned below. Thus, for example,cis/trans mixtures may be resolved into their cis and trans isomers andracemic compounds may be separated into their enantiomers.

The cis/trans mixtures may be resolved, for example, by chromatographyinto the cis and trans isomers thereof. The compounds of general formulaI which occur as racemates may be separated by methods known per se intotheir optical antipodes and diastereomeric mixtures of compounds ofgeneral formula I may be resolved into their diastereomers by takingadvantage of their different physico-chemical properties using methodsknown per se, e.g. chromatography and/or fractional crystallization; ifthe compounds obtained thereafter are racemates, they may be resolvedinto the enantiomers as mentioned below.

The racemates are preferably resolved by column chromatography on chiralphases or by crystallization from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as esters or amides with the racemic compound. Saltsmay be formed with enantiomerically pure acids for basic compounds andwith enantiomerically pure bases for acidic compounds. Diastereomericderivatives are formed with enantiomerically pure auxiliary compounds,e.g. acids, their activated derivatives, or alcohols. Separation of thediastereomeric mixture of salts or derivatives thus obtained may beachieved by taking advantage of their different physico-chemicalproperties, e.g. differences in solubility; the free antipodes may bereleased from the pure diastereomeric salts or derivatives by the actionof suitable agents. Optically active acids commonly used for such apurpose as well as optically active alcohols applicable as auxiliaryresidues are known to those skilled in the art.

As mentioned above, the compounds of formula I may be converted intosalts, particularly for pharmaceutical use into the pharmaceuticallyacceptable salts. As used herein, “pharmaceutically acceptable salts”refer to derivatives of the disclosed compounds wherein the parentcompound is modified by making acid or base salts thereof.

The compounds according to the invention are advantageously alsoobtainable using the methods described in the examples that follow,which may also be combined for this purpose with methods known to theskilled man from the literature.

Terms and Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

The terms “compound(s) according to this invention”, “compound(s) offormula (I)”, “compound(s) of the invention” and the like denote thecompounds of the formula (I) according to the present inventionincluding their tautomers, stereoisomers and mixtures thereof and thesalts thereof, in particular the pharmaceutically acceptable saltsthereof, and the solvates and hydrates of such compounds, including thesolvates and hydrates of such tautomers, stereoisomers and saltsthereof.

The terms “treatment” and “treating” embrace both preventative, i.e.prophylactic, or therapeutic, i.e. curative and/or palliative,treatment. Thus the terms “treatment” and “treating” comprisetherapeutic treatment of patients having already developed saidcondition, in particular in manifest form. Therapeutic treatment may besymptomatic treatment in order to relieve the symptoms of the specificindication or causal treatment in order to reverse or partially reversethe conditions of the indication or to stop or slow down progression ofthe disease. Thus the compositions and methods of the present inventionmay be used for instance as therapeutic treatment over a period of timeas well as for chronic therapy. In addition the terms “treatment” and“treating” comprise prophylactic treatment, i.e. a treatment of patientsat risk to develop a condition mentioned hereinbefore, thus reducingsaid risk.

When this invention refers to patients requiring treatment, it relatesprimarily to treatment in mammals, in particular humans.

The term “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease or condition, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease or condition,or (iii) prevents or delays the onset of one or more symptoms of theparticular disease or condition described herein.

The terms “modulated” or “modulating”, or “modulate(s)”, as used herein,unless otherwise indicated, refer to the activation of theG-protein-coupled receptor GPR40 with one or more compounds of thepresent invention.

The terms “mediated” or “mediating” or “mediate”, as used herein, unlessotherwise indicated, refer to the (i) treatment, including prevention ofthe particular disease or condition, (ii) attenuation, amelioration, orelimination of one or more symptoms of the particular disease orcondition, or (iii) prevention or delay of the onset of one or moresymptoms of the particular disease or condition described herein.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom, radical or moiety is replaced with aselection from the indicated group, provided that the atom's normalvalence is not exceeded, and that the substitution results in anacceptably stable compound.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl-C₁₋₃-alkyl-” means an aryl group which is bound to aC₁₋₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula in case of any discrepancy the formulashall prevail.

An asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom whichis closest to the core or to the group to which the substituent isattached.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

In a definition of a group the term “wherein each X, Y and Z group isoptionally substituted with” and the like denotes that each group X,each group Y and each group Z either each as a separate group or each aspart of a composed group may be substituted as defined. For example adefinition “R^(ex) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyl or C₁₋₃-alkyl-O—, wherein each alkyl group isoptionally substituted with one or more L^(ex).” or the like means thatin each of the beforementioned groups which comprise the term alkyl,i.e. in each of the groups C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl andC₁₋₃-alkyl-O—, the alkyl moiety may be substituted with L^(ex) asdefined.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts) also comprise a part of the invention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer from 1 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer 1 to n, either aloneor in combination with another radical, denotes an acyclic, straight orbranched chain divalent alkyl radical containing from 1 to n carbonatoms. For example the term C₁₋₄-alkylene includes —(CH₂)—, —(CH₂—CH₂)—,—(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

The term “C_(2-n)-alkenyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenyl includes —CH═CH₂,—CH═CH—CH₃, —CH₂—CH═CH₂.

The term “C_(2-n)-alkynyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynyl includes —C—CH,—C≡C—CH₃, —CH₂—C≡CH.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer 4 to n, eitheralone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Thecyclic group may be mono-, bi-, tri- or spirocyclic, most preferablymonocyclic. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclo-pentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl,norpinyl, norbonyl, norcaryl, adamantyl, etc.

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

Pharmacological Activity

The activity of the compounds of the invention may be demonstrated usingthe following assay:

IP₁ accumulation measurements using the IPOne assay system—1321N1 cellsstably expressing human GPR40 receptor (Euroscreen, Belgium) are seeded24 h before the assay in white 384-well plates in culture mediumcontaining 10% FCS, 1% Na-Pyruvate and 400 μg/mL G418. IP₁ is assayedaccording to the manufacturer's description (Cisbio Bioassays, France).In brief, the assay is started by substitution of the culture medium bystimulation buffer (Hepes 10 mM, CaCl₂) 1 mM, MgCl₂ 0.5 mM, KCl 4.2 mM,NaCl 146 mM, glucose 5.5 mM and LiCl 50 mM, pH 7.4). Cells arestimulated for 1 h at 37° C., 5% CO₂ by addition of the compounds thatare diluted in stimulation buffer containing LiCl. Assays are stopped byadding HTRF-conjugates (IP1-d2 and Anti-IP1 cryptate Tb) and lysisbuffer, provided by the manufacturer. After an incubation time of 1 h atroom temperature plates are measured using an EnVision™, Perkin Elmer.The obtained fluorescence ratios at 665/615 nM are then used tocalculate the pEC₅₀ values using Assay Explorer 3.3 Software (Accelrys,Inc.) by interpolation using an IP1 reference curve and subsequentsigmoidal curve fitting allowing for a variable hill slope.

The compounds according to the invention typically have EC₅₀ values inthe range from about 1 nM to about 10 μM, preferably less than 1 μM,more preferably less than 100 nM.

EC₅₀ values for compounds according to the invention are shown in thefollowing table. The number of the compound corresponds to the number ofthe Example in the experimental section.

TABLE 2 EC₅₀ EC₅₀ EC₅₀ EC₅₀ Example [nM] Example [nM] Example [nM]Example [nM] 1 5 2 6 3 19 4 15 5 11 6 9 7 11 8 6 9 62 10 23 11 32 12 2713 29 14 27 15 24 16 37 17 3 18 6 19 7 20 5 21 6 22 4 23 24 24 2124 2536 26 12 28 4 29 10 30 12Solubility

The aqueous solubility of the compounds of the invention is determinedby comparing the amount dissolved in buffer to the amount in anacetonitrile/water (1/1) solution. Starting from a 10 mM DMSO stocksolution aliquots are diluted with acetonitrile/water (1/1) or buffer,respectively. After 24 h of shaking, the solutions are filtrated andanalyzed by LC-UV. The amount dissolved in buffer is compared to theamount in the acetonitrile solution.

Solubility is usually being measured from 0.001 to 0.125 mg/mL at a DMSOconcentration of 2.5%. If more than 90% of the compound is dissolved inbuffer, the value is marked with “>”.

The compounds of the invention show higher solubility at low (pH 2.2)and medium pH value (pH 6.8) compared with their structural counterpartsexplicitly disclosed in WO 2013/178575. Their development andapplication is therefore more convenient and reliable. The followingcompilation shows the superiority of the compounds of this invention interms of solubility at pH 2.2 and pH 6.8 by comparing selected compoundsof this invention with their analogs from WO 2013/178575.

Example 3 in this invention: Example 17 in WO 2013/178575:

Solubility at pH 2.2: 24 μg/mL Solubility at pH 2.2: <1 μg/mL Solubilityat pH 6.8: 40 μg/mL Solubility at pH 6.8: <1 μg/mL Example 1 in thisinvention: Example 45 in WO 2013/178575:

Solubility at pH 2.2: 7 μg/mL Solubility at pH 2.2: <1 μg/mL Solubilityat pH 6.8: 19 μg/mL Solubility at pH 6.8: <1 μg/mL

In view of their ability to modulate the activity of theG-protein-coupled receptor GPR40, in particular an agonistic activity,the compounds of general formula I according to the invention, includingthe corresponding salts thereof, are theoretically suitable for thetreatment of all those diseases or conditions which may be affected orwhich are mediated by the activation of the G-protein-coupled receptorGPR40.

Accordingly, the present invention relates to a compound of generalformula I as a medicament.

Furthermore, the present invention relates to the use of a compound ofgeneral formula I or a pharmaceutical composition according to thisinvention for the treatment and/or prevention of diseases or conditionswhich are mediated by the activation of the G-protein-coupled receptorGPR40 in a patient, preferably in a human.

In yet another aspect the present invention relates to a method fortreating a disease or condition mediated by the activation of theG-protein-coupled receptor GPR40 in a mammal that includes the step ofadministering to a patient, preferably a human, in need of suchtreatment a therapeutically effective amount of a compound or apharmaceutical composition of the present invention.

Diseases and conditions mediated by agonists of the G-protein-coupledreceptor GPR40 embrace metabolic diseases or conditions. According toone aspect the compounds and pharmaceutical compositions of the presentinvention are particularly suitable for treating diabetes mellitus, inparticular Type 2 diabetes, Type 1 diabetes, complications of diabetes(such as e.g. retinopathy, nephropathy or neuropathies, diabetic foot,ulcers or macroangiopathies), metabolic acidosis or ketosis, reactivehypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulinresistance, metabolic syndrome, dyslipidaemias of different origins,atherosclerosis and related diseases, obesity, high blood pressure,chronic heart failure, oedema and hyperuricaemia.

The compounds and pharmaceutical compositions of the present inventionare also suitable for preventing beta-cell degeneration such as e.g.apoptosis or necrosis of pancreatic beta cells. The compounds andpharmaceutical compositions of the present invention are also suitablefor improving or restoring the functionality of pancreatic cells, andalso for increasing the number and size of pancreatic beta cells.

Therefore according to another aspect the invention relates to compoundsof formula I and pharmaceutical compositions according to the inventionfor use in preventing, delaying, slowing the progression of and/ortreating metabolic diseases, particularly in improving the glycaemiccontrol and/or beta cell function in the patient.

In another aspect the invention relates to compounds of formula I andpharmaceutical compositions according to the invention for use inpreventing, delaying, slowing the progression of and/or treating type 2diabetes, overweight, obesity, complications of diabetes and associatedpathological conditions.

In addition the compounds and pharmaceutical compositions according tothe invention are suitable for use in one or more of the followingtherapeutic processes:

-   -   for preventing, delaying, slowing the progression of or treating        metabolic diseases, such as for example type 1 diabetes, type 2        diabetes, insufficient glucose tolerance, insulin resistance,        hyperglycaemia, hyperlipidaemia, hypercholesterolaemia,        dyslipidaemia, syndrome X, metabolic syndrome, obesity, high        blood pressure, chronic systemic inflammation, retinopathy,        neuropathy, nephropathy, atherosclerosis, endothelial        dysfunction or bone-related diseases (such as osteoporosis,        rheumatoid arthritis or osteoarthritis);    -   for improving glycaemic control and/or reducing fasting plasma        glucose, postprandial plasma glucose and/or the glycosylated        haemoglobin HbA1c;    -   for preventing, delaying, slowing or reversing the progression        of disrupted glucose tolerance, insulin resistance and/or        metabolic syndrome to type 2 diabetes;    -   for preventing, delaying, slowing the progression of or treating        a condition or a disease selected from among the complications        of diabetes, such as for example retinopathy, nephropathy or        neuropathies, diabetic foot, ulcers or macroangiopathies;    -   for reducing weight or preventing weight gain or assisting        weight loss;    -   for preventing or treating the degradation of pancreatic beta        cells and/or improving and/or restoring the functionality of        pancreatic beta cells and/or restoring the functionality of        pancreatic insulin secretion;    -   for maintaining and/or improving insulin sensitivity and/or        preventing or treating hyperinsulinaemia and/or insulin        resistance.

In particular, the compounds and pharmaceutical compositions accordingto the invention are suitable for the treatment of obesity, diabetes(comprising type 1 and type 2 diabetes, preferably type 2 diabetesmellitus) and/or complications of diabetes (such as for exampleretinopathy, nephropathy or neuropathies, diabetic foot, ulcers ormacroangiopathies).

The compounds according to the invention are most particularly suitablefor treating type 2 diabetes mellitus.

The dose range of the compounds of general formula I applicable per dayis usually from 0.001 to 10 mg per kg body weight, for example from 0.01to 8 mg per kg body weight of the patient. Each dosage unit mayconveniently contain from 0.1 to 1000 mg, for example 0.5 to 500 mg.

The actual therapeutically effective amount or therapeutic dosage willof course depend on factors known by those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the compound or composition will be administered atdosages and in a manner which allows a therapeutically effective amountto be delivered based upon patient's unique condition.

The compounds, compositions, including any combinations with one or moreadditional therapeutic agents, according to the invention may beadministered by oral, transdermal, inhalative, parenteral or sublingualroute. Of the possible methods of administration, oral or intravenousadministration is preferred.

Pharmaceutical Compositions

Suitable preparations for administering the compounds of formula I,optionally in combination with one or more further therapeutic agents,will be apparent to those with ordinary skill in the art and include forexample tablets, pills, capsules, suppositories, lozenges, troches,solutions, syrups, elixirs, sachets, injectables, inhalatives andpowders etc. Oral formulations, particularly solid forms such as e.g.tablets or capsules are preferred. The content of the pharmaceuticallyactive compound(s) is advantageously in the range from 0.1 to 90 wt.-%,for example from 1 to 70 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or morecompounds according to formula I with known excipients, for exampleinert diluents, carriers, disintegrants, adjuvants, surfactants, bindersand/or lubricants. The tablets may also consist of several layers. Theparticular excipients, carriers and/or diluents that are suitable forthe desired preparations will be familiar to the skilled man on thebasis of his specialist knowledge. The preferred ones are those that aresuitable for the particular formulation and method of administrationthat are desired. The preparations or formulations according to theinvention may be prepared using methods known per se that are familiarto the skilled man, such as for example by mixing or combining at leastone compound of formula I according to the invention, or apharmaceutically acceptable salt of such a compound, and one or moreexcipients, carriers and/or diluents.

Combination Therapy

The compounds of the invention may further be combined with one or more,preferably one additional therapeutic agent. According to one embodimentthe additional therapeutic agent is selected from the group oftherapeutic agents useful in the treatment of diseases or conditionsdescribed hereinbefore, in particular associated with metabolic diseasesor conditions such as for example diabetes mellitus, obesity, diabeticcomplications, hypertension, hyperlipidemia. Additional therapeuticagents which are suitable for such combinations include in particularthose which for example potentiate the therapeutic effect of one or moreactive substances with respect to one of the indications mentionedand/or which allow the dosage of one or more active substances to bereduced.

Therefore a compound of the invention may be combined with one or moreadditional therapeutic agents selected from the group consisting ofantidiabetic agents, agents for the treatment of overweight and/orobesity and agents for the treatment of high blood pressure, heartfailure and/or atherosclerosis.

Antidiabetic agents are for example metformin, sulphonylureas,nateglinide, repaglinide, thiazolidinediones, PPAR-(alpha, gamma oralpha/gamma) agonists or modulators, alpha-glucosidase inhibitors, DPPIVinhibitors, SGLT2-inhibitors, insulin and insulin analogues, GLP-1 andGLP-1 analogues or amylin and amylin analogues, cycloset, 11-HSDinhibitors. Other suitable combination partners are inhibitors ofprotein tyrosinephosphatase 1, substances that affect deregulatedglucose production in the liver, such as e.g. inhibitors ofglucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogenphosphorylase, glucagon receptor antagonists and inhibitors ofphosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvatedehydrokinase, alpha2-antagonists, CCR-2 antagonists or glucokinaseactivators. One or more lipid lowering agents are also suitable ascombination partners, such as for example HMG-CoA-reductase inhibitors,fibrates, nicotinic acid and the derivatives thereof, PPAR-(alpha, gammaor alpha/gamma) agonists or modulators, PPAR-delta agonists, ACATinhibitors or cholesterol absorption inhibitors such as, bileacid-binding substances such as, inhibitors of ileac bile acidtransport, MTP inhibitors, or HDL-raising compounds such as CETPinhibitors or ABC1 regulators.

Therapeutic agents for the treatment of overweight and/or obesity arefor example antagonists of the cannabinoid1 receptor, MCH-1 receptorantagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists,P3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor.

Therapeutic agents for the treatment of high blood pressure, chronicheart failure and/or atherosclerosis are for example A-II antagonists orACE inhibitors, ECE inhibitors, diuretics, β-blockers, Ca-antagonists,centrally acting antihypertensives, antagonists of thealpha-2-adrenergic receptor, inhibitors of neutral endopeptidase,thrombocyte aggregation inhibitors and others or combinations thereofare suitable. Angiotensin II receptor antagonists are preferably usedfor the treatment or prevention of high blood pressure and complicationsof diabetes, often combined with a diuretic such as hydrochlorothiazide.

The dosage for the combination partners mentioned above is usually 1/5of the lowest dose normally recommended up to 1/1 of the normallyrecommended dose.

Preferably, compounds of the present invention and/or pharmaceuticalcompositions comprising a compound of the present invention optionallyin combination with one or more additional therapeutic agents areadministered in conjunction with exercise and/or a diet.

Therefore, in another aspect, this invention relates to the use of acompound according to the invention in combination with one or moreadditional therapeutic agents described hereinbefore and hereinafter forthe treatment of diseases or conditions which may be affected or whichare mediated by the activation of the G-protein-coupled receptor GPR40,in particular diseases or conditions as described hereinbefore andhereinafter.

In yet another aspect the present invention relates a method fortreating a disease or condition mediated by the activation of theG-protein-coupled receptor GPR40 in a patient that includes the step ofadministering to the patient, preferably a human, in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention in combination with a therapeutically effective amountof one or more additional therapeutic agents described in hereinbeforeand hereinafter.

The use of the compound according to the invention in combination withthe additional therapeutic agent may take place simultaneously or atstaggered times.

The compound according to the invention and the one or more additionaltherapeutic agents may both be present together in one formulation, forexample a tablet or capsule, or separately in two identical or differentformulations, for example as a so-called kit-of-parts.

Consequently, in another aspect, this invention relates to apharmaceutical composition which comprises a compound according to theinvention and one or more additional therapeutic agents describedhereinbefore and hereinafter, optionally together with one or more inertcarriers and/or diluents.

Other features and advantages of the present invention will becomeapparent from the following more detailed Examples which illustrate, byway of example, the principles of the invention.

EXAMPLES

The terms “ambient temperature” and “room temperature” are usedinterchangeably and designate a temperature of about 20° C.

As a rule, ¹H-NMR and/or mass spectra have been obtained for thecompounds prepared.

Intermediates and Examples reported in the following bearing a basic oracidic group may be obtained as a corresponding salt or neutral compounddepending on the purification method and conditions employed. Salts canbe transformed into their neutral counterparts by standard proceduresknown to the one skilled in the art.

Analytical HPLC Parameters Employed for Characterization of Products(TFA Denotes Trifluoroacetic Acid):

Method: 1 Device Agilent 1200 with DA- and MS-Detector Column: SunfireC18, 3 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ % SolventTemper- Solvent Time [H₂O, % Solvent Flow ature [min] 0.1% TFA][Acetonitrile] [ml/min] [° C.] 0.00 97  3 2.2 60 0.20 97  3 2.2 60 1.20 0 100 2.2 60 1.25  0 100 3 60 1.40  0 100 3 60

Method: 2 Device Waters Acquity, QDa Detector Column: Sunfire C18, 3 ×30 mm, 2.5 μm Column Supplier: Waters Gradient/ % Solvent % SolventTemper- Solvent Time [H₂O, [Acetonitrile Flow ature [min] 0.1% TFA]0.08% TFA] [ml/min] [° C.] 0 95  5 1.5 60 1.3  0 100 1.5 60 1.5  0 1001.5 60 1.6 95  5 1.5 60

Intermediate 1 trans-2-(5-Bromo-pyridin-2-yl)-cyclopropanecarboxylicAcid Ethyl Ester

Step 1: 5-Bromo-2-vinyl-pyridine

Na₂CO₃ solution (2 mol/L in water, 8.8 mL) is added to a flask chargedwith a stir bar, 2-iodo-5-bromo-pyridine (2.00 g), potassiumvinyltrifluoroborate (0.94 g), tetrahydrofuran (6 mL), and toluene (2mL) at room temperature. The mixture is purged with Ar for 5 min priorto the addition of1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) (0.49 g). Themixture is stirred at 100° C. overnight. After cooling to roomtemperature, aqueous NH₄Cl solution is added, and the resulting mixtureis extracted with ethyl acetate. The combined extract is dried (MgSO₄)and concentrated. The residue is chromatographed on silica gel(cyclohexane/ethyl acetate 4:1→7:3) to give the title compound. Massspectrum (ESI⁺): m/z=184/186 (Br) [M+H]+.

Step 2: trans-2-(5-Bromo-pyridin-2-yl)-cyclopropanecarboxylic Acid EthylEster

5,10,15,20-Tetraphenyl-21H,23H-porphine cobalt(II) (28 mg),1-methylimidazole (0.52 g), and ethyl diazoacetate (13% indichloromethane; 2.0 mL) are added to a flask charged with a stir bar,5-bromo-2-vinyl-pyridine (0.39 g), and toluene (3.3 mL) at roomtemperature. The mixture is stirred at room temperature for 5 min andthen at 80° C. for 90 min. After cooling to room temperature, themixture is concentrated, and the residue is chromatographed on silicagel (cyclohexane/ethyl acetate 6:1-3:2) to give the racemic transconfigured title compound. Mass spectrum (ESI⁺): m/z=270/272 (Br)[M+H]+.

Intermediate 2 (1S,2S)-2-(5-Bromo-pyridin-2-yl)-cyclopropanecarboxylicAcid Ethyl Ester

Step 1: 1-(5-Bromo-pyridin-2-yl)-2-chloro-ethanone

^(i)PrMgCl*LiCl (Turbo Grignard, 1.3 mol/L in tetrahydrofuran, 25.6 mL)is added dropwise to a flask charged with a stir bar,2-iodo-5-bromo-pyridine (9.00 g), and tetrahydrofuran (180 mL) andchilled to −30° C. The mixture is stirred in the cooling bath for 1 h.2-Chloro-N-methoxy-N-methylacetamide (4.58 g) dissolved intetrahydrofuran (20 mL) is added dropwise over 5 min. The mixture isstirred for 30 min and then quenched by the addition of aqueous 1 M HClsolution. The mixture is concentrated, and the aqueous residue isextracted with ethyl acetate. The combined extract is dried (MgSO₄) andconcentrated. The residue is chromatographed on silica gel(cyclohexane/ethyl acetate 20:1-1:1) to give the title compound. Massspectrum (ESI⁺): m/z=234/236/238 (Br+Cl) [M+H]⁺.

Step 2: (R)-1-(5-Bromo-pyridin-2-yl)-2-chloro-ethanol

Formic acid (3.9 mL) is added to a flask charged with a stir bar andtriethylamine (14.3 mL) and chilled in an ice bath. The mixture isstirred for 10 min and then added dropwise over 5 min to a flask chargedwith 1-(5-bromo-pyridin-2-yl)-2-chloro-ethanone (4.80 g),(1S,2S)-Cp*RhCl(TsNCHPhCHPhNH₂) (0.13 g; prepared from(1S,2S)-(+)—N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine andpentamethyl-cyclopentadienyl-rhodium chloride dimer as described in,e.g., Organometallics 2009, 28, 1435-1446 or Chem. Commun. 2015, 52,362-365; alternatively, the catalyst is prepared in situ by combiningthe two components in the reaction flask), and ethyl acetate (150 ml) at−45° C. The mixture is stirred at −30° C. for 90 min. Aqueous NaHCO₃solution is added, and the resulting mixture is stirred at roomtemperature. The mixture is extracted with ethyl acetate, and thecombined extract is dried (MgSO₄) and concentrated. The residue ischromatographed on silica gel (cyclohexane/ethyl acetate 50:1→6:1) togive the title compound with an enantiomeric excess (ee) of 75 to 95%.Mass spectrum (ESI⁺): m/z=236/238/240 (Br+Cl) [M+H]⁺.

Step 3: (R)-5-Bromo-2-oxiranyl-pyridine

Aqueous NaOH solution (4 mol/L, 25 mL) is added to a flask charged witha stir bar, (R)-1-(5-bromo-pyridin-2-yl)-2-chloro-ethanol (3.0 g), andtetrahydrofuran (100 mL) at room temperature. The mixture is stirredovernight prior to the addition of brine. The organic phase isseparated, and the aqueous phase is extracted twice withtetrahydrofuran. The combined organic phase is dried (MgSO₄) andconcentrated to give the crude title compound that is used as is in thefollowing step. Mass spectrum (ESI⁺): m/z=200/202 (Br) [M+H]⁺.

Step 4: (1S,2S)-2-(5-Bromo-pyridin-2-yl)-cyclopropanecarboxylic AcidEthyl Ester

A solution of sodium tert-butoxide (7.9 g) in tetrahydrofuran (80 mL) isadded dropwise over 30 min to a flask charged with a stir bar,triethylphosphonoacetate (16.3 mL), and toluene (80 mL) at roomtemperature. The mixture is stirred for 30 min and then added dropwiseover 4 h to a solution of (R)-5-bromo-2-oxiranyl-pyridine (5.5 g) intoluene (350 mL) at 90° C. The mixture is stirred for 1 h and thencooled to room temperature. The mixture is washed with aqueous 1 M H₃PO₄solution and brine and dried (MgSO₄). The mixture is concentrated, andthe residue is chromatographed on silica gel (MPLC, petrol ether/ethylacetate) to give the title compound. Mass spectrum (ESI⁺): m/z=270/272(Br) [M+H]⁺.

Intermediate 3 (1S,2S)-2-(5-Bromo-pyridin-2-yl)-cyclopropanecarboxylicAcid

Aqueous 4 M NaOH solution (7.3 mL) is added to a flask charged with astir bar, (1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acidethyl ester (4.89 g), and tetrahydrofuran (30 mL) at room temperature.The mixture is stirred at 60° C. for 4 h. After cooling to roomtemperature, water is added and most of the tetrahydrofuran isevaporated. Aqueous 4 M HCl solution is added dropwise to adjust the pHvalue to ca. 4. The mixture is stirred overnight. The precipitate isseparated by filtration, washed with water, and dried in a desiccator togive the title compound.

The enantiomeric purities (ee) of batches of Intermediate 3, obtainedfrom Intermediate 2 and hydrolyzed as described above, are commonlybetween 75% and 95%.

The enantiomeric purity of batches of Intermediate 3 may be increasedto >95% ee by employing the following procedure:

(S)-1-Phenylethylamine (1.85 mL) is added to a solution of(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid (3.51 g) inisopropanol (55 mL) at 80° C. The solution is stirred for 15 min andthen left standing without stirring at room temperature overnight. Theprecipitate is separated by filtration, washed with isopropanol, anddried at 40° C. to give the (S)-1-phenylethylammonium(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylate (if thediastereomeric purity of the ammonium salt is still not sufficient theprecipitate is again recrystallized from isopropanol).

The ammonium carboxylate (2.79 g) is suspended in ethyl acetate (50 mL),and aqueous 4 M HCl solution (7.7 mL) is added. The mixture is stirreduntil all solid is dissolved. The organic phase is separated and washedwith 4 M HCl solution, water, and brine. The organic phase is dried(MgSO₄) and concentrated to give one batch of(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid. Theaqueous phase is freeze-dried and then chromatographed on silica gel(dichloromethane/methanol) to give another batch of(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid.

Intermediate 4 (1S,2S)-2-(5-Bromo-pyridin-2-yl)-cyclopropanecarboxylicAcid Methyl Ester

SOCl₂ (2.7 mL) is added to a flask charged with a stir bar,(S)-1-phenylethylammonium(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylate (12.2 g), andmethanol (150 mL) at room temperature. The mixture is stirred at roomtemperature overnight. The solution is concentrated, and the residue istaken up in dichloromethane. The organic phase is washed with 1 Maqueous NaHCO₃ solution and brine, dried (MgSO₄), and concentrated. Theresidue is chromatographed on silica gel (petrol ether/ethyl acetate85→15) to give the title compound. Mass spectrum (ESI⁺): m/z=256/258(Br) [M+H]⁺.

Intermediate 5(1S,2S)-2-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-cyclopropanecarboxylicAcid Ethyl Ester

A flask charged with a stir bar,(1S,2S)-2-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid ethyl ester(1.20 g), bis(pinacolato)diboron (1.37 g), potassium acetate (1.09 g),and 1,4-dioxane (15 mL) is purged with Ar for 10 min.1,1′-Bis(diphenylphosphino)ferrocene-dichloropalladium(II)dichloromethane complex (0.18 g) is added, and the mixture is stirred at100° C. for 3.5 h. After cooling to room temperature, the mixture isdiluted with aqueous NH₄Cl solution and extracted with ethyl acetate.The combined organic phase is washed with brine, dried (MgSO₄), andconcentrated to give the crude title compound that is used as is in thenext reaction step.

Intermediate 6 (1S,2S)-2-(5-Hydroxy-pyridin-2-yl)-cyclopropanecarboxylicAcid Ethyl Ester

Hydrochloric acid (4 mol/L in water; 1.75 mL) and hydrogen peroxide (35%in water; 2.40 mL) are added in the given order to a flask charged witha stir bar,(1S,2S)-2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-cyclopropanecarboxylicacid ethyl ester (2.20 g), and acetic acid (15 mL) chilled in an icebath. The cooling bath is removed, and the mixture is stirred at roomtemperature for 1 h. Ethyl acetate is added, and the resulting mixtureis washed with water and brine, dried (MgSO₄), and concentrated. Theresidue is chromatographed on silica gel (petrol ether/ethyl acetate) togive the title compound. Mass spectrum (ESI⁺): m/z=208 [M+H]⁺.

Intermediate 7(1S,2S)-2-{5-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid Ethyl Ester

K₂CO₃ (1.25 g) and2-(3-bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.10g) are added in the given order to a flask charged with a stir bar,(1S,2S)-2-(5-hydroxy-pyridin-2-yl)-cyclopropanecarboxylic acid ethylester (0.83 g), and N,N-dimethylformamide (15 mL) at room temperature.The mixture is stirred at room temperature overnight. Water is added,and the resulting mixture is extracted with ethyl acetate. The combinedorganic extracts are washed with brine, dried (MgSO₄), and concentrated.The residue is chromatographed on silica gel (cyclohexane/ethyl acetate9:1→2:1) to give the title compound. Mass spectrum (ESI⁺): m/z=424[M+H]⁺.

Intermediate 8(1S,2S)-2-[5-(5-Bromo-2-fluoro-benzyloxy)-pyridin-2-yl]-cyclopropanecarboxylicAcid Ethyl Ester

The title compound is prepared from(1S,2S)-2-(5-hydroxy-pyridin-2-yl)-cyclopropanecarboxylic acid ethylester and 4-bromo-2-bromomethyl-1-fluoro-benzene following a procedureanalogous to that described for Intermediate 7; Cs₂CO₃ instead of K₂CO₃is used. Mass spectrum (ESI⁺): m/z=394/396 (Br) [M+H]⁺.

Intermediate 9(1S,2S)-2-{5-[2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid Ethyl Ester

A flask charged with a stir bar,(1S,2S)-2-[5-(5-bromo-2-fluoro-benzyloxy)-pyridin-2-yl]-cyclopropanecarboxylicacid ethyl ester (0.68 g), bis(pinacolato)diboron (0.52 g), potassiumacetate (0.68 g), and 1,4-dioxane (5 mL) is purged with Ar for 10 min.1,1′-Bis(diphenylphosphino)ferrocene-dichloropalladium(II) (60 mg) isadded, and the mixture is stirred at 100° C. for 2 h. After cooling toroom temperature, the mixture is diluted with water and extracted withethyl acetate. The combined organic phase is treated with charcoal,filtered, and concentrated. The residue is chromatographed on silica gel(petrol ether/ethyl acetate) to give the title compound. Mass spectrum(ESI⁺): m/z=442 [M+H]⁺.

Intermediate 10(1S,2S)-2-[5-(5-Bromo-2,4-difluoro-benzyloxy)-pyridin-2-yl]-cyclopropanecarboxylicAcid Ethyl Ester

Di-tert-butyl azodicarboxylate (20% in toluene, 0.57 g) is added over 5min to a flask charged with a stir bar,(5-bromo-2,4-difluoro-phenyl)-methanol (0.10 g),(1S,2S)-2-(5-hydroxy-pyridin-2-yl)-cyclopropanecarboxylic acid ethylester (0.10 g), tri-n-butyl-phosphane (140 μL), and tetrahydrofuran (2mL) chilled in an ice bath. The mixture is stirred for 45 min. AqueousNaHCO₃ solution is added, and the resulting mixture is extracted withethyl acetate. The combined organic extracts are washed with brine,dried (MgSO₄), and concentrated. The residue is chromatographed onsilica gel (petrol ether/ethyl acetate) to give the title compound. Massspectrum (ESI⁺): m/z=412/414 (Br) [M+H]⁺.

Intermediate 11(1S,2S)-2-[5-(3-Bromo-4-trifluoromethyl-benzyloxy)-pyridin-2-yl]-cyclopropane-carboxylicAcid Ethyl Ester

The title compound is prepared from(1S,2S)-2-(5-hydroxy-pyridin-2-yl)-cyclopropanecarboxylic acid ethylester and (3-bromo-4-trifluoromethyl-phenyl)-methanol following aprocedure analogous to that described for Intermediate 10. Mass spectrum(ESI⁺): m/z=444/446 (Br) [M+H]⁺.

Example 1(1S,2S)-2-{5-[2′,6′-Dimethyl-4′-(2-methyl-2H-tetrazol-5-yl)-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

A vial charged with a stir bar,(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester (50 mg),5-(4-bromo-3,5-dimethyl-phenyl)-2-methyl-2H-tetrazole (32 mg), K₃PO₄ (1mol/L in water; 0.59 mL), and 1,4-dioxane (1.5 mL) is purged with Ar for10 min.Bis[di-tert-butyl-(4-dimethylaminophenyl)-phosphine]dichloropalladium(II)(PdCl₂(Amphos)₂; 3 mg) is added, and the mixture is stirred at 90° C.for 1 h. After cooling to room temperature, aqueous 4 M NaOH solution(0.5 mL) and methanol (1 mL) are added, and the mixture is stirred at40° C. for 0.5 h. After cooling to room temperature, the mixture isacidified with aqueous 4 M HCl solution, filtered, and submitted to HPLC(MeCN/H₂O/F₃CCO₂H as eluent) to give the title compound. LC (method 1):t_(R)=0.99 min; Mass spectrum (ESI⁺): m/z=456 [M+H]⁺.

Example 2(1S,2S)-2-{5-[2′,6′-Dimethyl-4′-(5-methyl-pyrimidin-2-yl)-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and2-(4-chloro-3,5-dimethyl-phenyl)-5-methyl-pyrimidine following aprocedure analogous to that described for Example 1. LC (method 1):t_(R)=1.03 min; Mass spectrum (ESI⁺): m/z=466 [M+H]⁺.

Example 3(1S,2S)-2-{5-[4′-(3-Hydroxy-3-methyl-butoxy)-2′,6′-dimethyl-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and4-(4-bromo-3,5-dimethyl-phenoxy)-2-methyl-butan-2-ol following aprocedure analogous to that described for Example 1. LC (method 1):t_(R)=1.00 min; Mass spectrum (ESI⁺): m/z=476 [M+H]⁺.

Example 4(1S,2S)-2-{5-[2′,6′-Dimethyl-4′-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and5-(4-bromo-3,5-dimethyl-phenyl)-1-methyl-1H-pyridin-2-one following aprocedure analogous to that described for Example 1. LC (method 1):t_(R)=1.08 min; Mass spectrum (ESI⁺): m/z=481 [M+H]⁺.

Example 5(1S,2S)-2-[5-(2′,6′-Dimethyl-4′-pyrazin-2-yl-biphenyl-3-ylmethoxy)-pyridin-2-yl]-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and 2-(4-chloro-3,5-dimethyl-phenyl)-pyrazine followinga procedure analogous to that described for Example 1. LC (method 1):t_(R)=0.99 min; Mass spectrum (ESI⁺): m/z=452 [M+H]⁺.

Example 6(1S,2S)-2-(5-{4′-[2-(2-Hydroxy-2-methyl-propyl)-2H-tetrazol-5-yl]-2′,6′-dimethyl-biphenyl-3-ylmethoxy}-pyridin-2-yl)-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and1-[5-(4-bromo-3,5-dimethyl-phenyl)-tetrazol-2-yl]-2-methyl-propan-2-olfollowing a procedure analogous to that described for Example 1. LC(method 1): t_(R)=0.98 min; Mass spectrum (ESI⁺): m/z=514 [M+H]⁺.

Example 7(1S,2S)-2-{5-[2′,6′-Dimethyl-4′-(2-methyl-2H-pyrazol-3-yl)-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and5-(4-bromo-3,5-dimethyl-phenyl)-1-methyl-1H-pyrazole following aprocedure analogous to that described for Example 1. LC (method 1):t_(R)=0.99 min; Mass spectrum (ESI⁺): m/z=454 [M+H]⁺.

Example 8(1S,2S)-2-{5-[4′-(2-Methoxy-pyridin-4-yl)-2′,6′-dimethyl-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and 4-(4-bromo-3,5-dimethyl-phenyl)-2-methoxy-pyridinefollowing a procedure analogous to that described for Example 1. LC(method 1): t_(R)=1.00 min; Mass spectrum (ESI⁺): m/z=481 [M+H]⁺.

Example 9(1S,2S)-2-[5-(2′,6′-Diethyl-biphenyl-3-ylmethoxy)-pyridin-2-yl]-cyclopropane-carboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and 2-bromo-1,3-diethyl-benzene following a procedureanalogous to that described for Example 1. LC (method 2): t_(R)=0.87min; Mass spectrum (ESI⁺): m/z=402 [M+H]⁺.

Example 10(1S,2S)-2-{5-[2′,6′-Dimethyl-4′-(tetrahydro-pyran-4-ylmethoxy)-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and4-(4-bromo-3,5-dimethyl-phenoxymethyl)-tetrahydropyran following aprocedure analogous to that described for Example 1. LC (method 2):t_(R)=0.83 min; Mass spectrum (ESI⁺): m/z=488 [M+H]⁺.

Example 11(1S,2S)-2-{5-[2′,6′-Dimethyl-4′-(tetrahydro-furan-2-ylmethoxy)-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and2-(4-bromo-3,5-dimethyl-phenoxymethyl)-tetrahydrofuran following aprocedure analogous to that described for Example 1. LC (method 2):t_(R)=0.80 min; Mass spectrum (ESI⁺): m/z=474 [M+H]⁺.

Example 12(1S,2S)-2-(5-{2′,6′-Dimethyl-4′-[(S)-(tetrahydrofuran-3-yl)oxy]-biphenyl-3-ylmethoxy}-pyridin-2-yl)-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and(S)-3-(4-bromo-3,5-dimethyl-phenoxy)-tetrahydrofuran following aprocedure analogous to that described for Example 1. LC (method 2):t_(R)=0.76 min; Mass spectrum (ESI⁺): m/z=460 [M+H]⁺.

Example 13(1S,2S)-2-{5-[2′,6′-Dimethyl-4′-(tetrahydro-pyran-4-yloxy)-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and 4-(4-bromo-3,5-dimethyl-phenoxy)-tetrahydropyranfollowing a procedure analogous to that described for Example 1. LC(method 2): t_(R)=0.79 min; Mass spectrum (ESI⁺): m/z=474 [M+H]⁺.

Example 14(1S,2S)-2-[5-(4′-Methoxy-2′,6′-dimethyl-biphenyl-3-ylmethoxy)-pyridin-2-yl]-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and 4-bromo-3,5-dimethyl-anisole following a procedureanalogous to that described for Example 1. LC (method 2): t_(R)=0.79min; Mass spectrum (ESI⁺): m/z=404 [M+H]⁺.

Example 15(1S,2S)-2-[5-(2′,6′-Dichloro-biphenyl-3-ylmethoxy)-pyridin-2-yl]-cyclopropane-carboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and 2,6-dichloro-iodobenzene following a procedureanalogous to that described for Example 1. LC (method 2): t_(R)=0.77min; Mass spectrum (ESI⁺): m/z=414/416/418 (2 Cl) [M+H]⁺.

Example 16(1S,2S)-2-{5-[4′-(3-Methanesulfonyl-propoxy)-2′,6′-dimethyl-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and2-bromo-5-(3-methanesulfonyl-propoxy)-1,3-dimethyl-benzene following aprocedure analogous to that described for Example 1. LC (method 2):t_(R)=0.69 min; Mass spectrum (ESI⁺): m/z=510 [M+H]⁺.

Example 17(1S,2S)-2-{5-[4-Fluoro-2′,6′-dimethyl-4′-(2-methyl-2H-tetrazol-5-yl)-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

A vial charged with a stir bar,(1S,2S)-2-{5-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester (30 mg),5-(4-bromo-3,5-dimethyl-phenyl)-2-methyl-2H-tetrazole (22 mg),dicyclohexyl-(2′,6′-dimethoxy-biphenyl-2-yl)-phosphane (SPhos; 4 mg),K₃PO₄ (2 mol/L in water; 0.1 mL), and toluene (2 mL) is purged with Arfor 10 min. Palladium(II) acetate (1 mg) is added, and the mixture isstirred at 100° C. for 1 h. After cooling to room temperature, themixture is diluted with ethyl acetate and washed with water and brine.The solvent is evaporated, and the residue is taken up intetrahydrofuran (2 mL). Aqueous 4 M NaOH solution (0.5 mL) is added, andthe mixture is stirred at 100° C. overnight. After cooling to roomtemperature, acetic acid (0.12 mL) is added, and the resulting mixtureis concentrated. The residue is taken up in methanol and filtered. Thefiltrate is concentrated and submitted to HPLC (MeCN/H₂O/F₃CCO₂H aseluent) to give the title compound. LC (method 1): t_(R)=1.00 min; Massspectrum (ESI⁺): m/z=474 [M+H]⁺.

Example 18(1S,2S)-2-(5-{4-Fluoro-4′-[2-(2-hydroxy-2-methyl-propyl)-2H-tetrazol-5-yl]-2′,6′-dimethyl-biphenyl-3-ylmethoxy}-pyridin-2-yl)-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and1-[5-(4-bromo-3,5-dimethyl-phenyl)-tetrazol-2-yl]-2-methyl-propan-2-olfollowing a procedure analogous to that described for Example 17. LC(method 1): t_(R)=0.98 min; Mass spectrum (ESI⁺): m/z=532 [M+H]⁺.

Example 19(1S,2S)-2-[5-(4-Fluoro-2′,6′-dimethyl-4′-pyrazin-2-yl-biphenyl-3-ylmethoxy)-pyridin-2-yl]-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and 2-(4-chloro-3,5-dimethyl-phenyl)-pyrazine followinga procedure analogous to that described for Example 17; the couplingreaction is conducted with 1 mol % Pd(OAc)₂ and 2 mol % SPhos at 110° C.for 2 h. LC (method 1): t_(R)=0.99 min; Mass spectrum (ESI⁺): m/z=470[M+H]⁺.

Example 20(1S,2S)-2-{5-[4-Fluoro-4′-(2-methoxy-pyridin-4-yl)-2′,6′-dimethyl-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and 4-(4-bromo-3,5-dimethyl-phenyl)-2-methoxy-pyridinefollowing a procedure analogous to that described for Example 17; thecoupling reaction is conducted with 1 mol % Pd(OAc)₂ and 2 mol % SPhosat 110° C. for 2 h. LC (method 1): t_(R)=1.03 min; Mass spectrum (ESI⁺):m/z=499 [M+H]⁺.

Example 21(1S,2S)-2-{5-[4-Fluoro-2′,6′-dimethyl-4′-(2-methyl-2H-pyrazol-3-yl)-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and5-(4-bromo-3,5-dimethyl-phenyl)-1-methyl-1H-pyrazole following aprocedure analogous to that described for Example 17; the couplingreaction is conducted with 1 mol % Pd(OAc)₂ and 2 mol % SPhos at 110° C.for 2 h. LC (method 1): t_(R)=0.99 min; Mass spectrum (ESI⁺): m/z=472[M+H]⁺.

Example 22(1S,2S)-2-{5-[4-Fluoro-2′,6′-dimethyl-4′-(5-methyl-pyrimidin-2-yl)-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and2-(4-chloro-3,5-dimethyl-phenyl)-5-methyl-pyrimidine following aprocedure analogous to that described for Example 17; the couplingreaction is conducted with 1 mol % Pd(OAc)₂ and 2 mol % SPhos at 110° C.for 2 h. LC (method 1): t_(R)=1.04 min; Mass spectrum (ESI⁺): m/z=484[M+H]⁺.

Example 23(1S,2S)-2-{5-[4-Fluoro-2′,6′-dimethyl-4′-(3-methyl-oxetan-3-ylmethoxy)-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and3-(4-bromo-3,5-dimethyl-phenoxymethyl)-3-methyl-oxetane following aprocedure analogous to that described for Example 17; the couplingreaction is conducted with 1 mol % Pd(OAc)₂ and 2 mol % SPhos at 110° C.for 2 h. LC (method 1): t_(R)=1.04 min; Mass spectrum (ESI⁺): m/z=492[M+H]⁺.

Example 24(1S,2S)-3′-[6-(−2-Carboxy-cyclopropyl)-pyridin-3-yloxymethyl]-4′-fluoro-2,6-dimethyl-biphenyl-4-carboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and 4-bromo-3,5,N,N-tetramethyl-benzamide following aprocedure analogous to that described for Example 17; the couplingreaction is conducted with 1 mol % Pd(OAc)₂ and 2 mol % SPhos at 110° C.for 2 h, and the amide is saponified under treatment with aqueous NaOHat 100° C. LC (method 1): t_(R)=0.91 min; Mass spectrum (ESI⁺): m/z=436[M+H]⁺.

Example 25(1S,2S)-2-{5-[4-Fluoro-4′-(2-hydroxy-2-methyl-propoxy)-2′,6′-dimethyl-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and1-(4-bromo-3,5-dimethyl-phenoxy)-2-methyl-propan-2-ol following aprocedure analogous to that described for Example 17; the couplingreaction is conducted with 1 mol % Pd(OAc)₂ and 2 mol % SPhos at 110° C.for 2 h. LC (method 1): t_(R)=0.99 min; Mass spectrum (ESI⁺): m/z=480[M+H]⁺.

Example 26(1S,2S)-2-{5-[4,6-Difluoro-4′-(3-hydroxy-3-methyl-butoxy)-2′,6′-dimethyl-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-[5-(5-bromo-2,4-difluoro-benzyloxy)-pyridin-2-yl]-cyclopropanecarboxylicacid ethyl ester and4-(3-hydroxy-3-methyl-butoxy)-2,6-dimethyl-phenylboronic acid followinga procedure analogous to that described for Example 17; the couplingreaction is conducted with 1 mol % Pd(OAc)₂ and 2 mol % SPhos at 110° C.for 2 h. LC (method 1): t_(R)=1.01 min; Mass spectrum (ESI⁺): m/z=512[M+H]⁺.

Example 27(1S,2S)-2-[5-(4′-Dimethylcarbamoyl-4-fluoro-2′,6′-dimethyl-biphenyl-3-ylmethoxy)-pyridin-2-yl]-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-{5-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-pyridin-2-yl}-cyclopropanecarboxylicacid ethyl ester and 4-bromo-3,5,N,N-tetramethyl-benzamide following aprocedure analogous to that described for Example 17; the couplingreaction is conducted with 1 mol % Pd(OAc)₂ and 2 mol % SPhos at 110° C.for 2 h, and the selective saponification of the ester group is donewith 0.5 mol/L KOH in ethanol and tetrahydrofuran (1:1) at 50° C. LC(method 1): t_(R)=0.91 min; Mass spectrum (ESI⁺): m/z=463 [M+H]⁺.

Example 28(1S,2S)-2-{5-[4′-(5-Methoxy-pyrimidin-2-yl)-6-trifluoromethyl-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-[5-(3-bromo-4-trifluoromethyl-benzyloxy)-pyridin-2-yl]-cyclopropanecarboxylicacid ethyl ester and 4-(5-methoxy-pyrimidin-2-yl)-phenylboronic acidfollowing a procedure analogous to that described for Example 17; thecoupling reaction is conducted with 1 mol % Pd(OAc)₂ and 2 mol % SPhosat 110° C. for 2 h, and saponification is done with 0.5 mol/L KOH inethanol and tetrahydrofuran (1:1) at 50° C. LC (method 1): t_(R)=1.03min; Mass spectrum (ESI⁺): m/z=522 [M+H]⁺.

Example 29(1S,2S)-2-{5-[4′-(6-Methoxy-pyridazin-3-yl)-6-trifluoromethyl-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-[5-(3-bromo-4-trifluoromethyl-benzyloxy)-pyridin-2-yl]-cyclopropanecarboxylicacid ethyl ester and 4-(6-methoxy-pyridazin-3-yl)-phenylboronic acidfollowing a procedure analogous to that described for Example 17; thecoupling reaction is conducted with 1 mol % Pd(OAc)₂ and 2 mol % SPhosat 110° C. for 2 h, and saponification is done with 0.5 mol/L KOH inethanol and tetrahydrofuran (1:1) at 50° C. LC (method 1): t_(R)=0.99min; Mass spectrum (ESI⁺): m/z=522 [M+H]⁺.

Example 30(1S,2S)-2-{5-[4′-(3-Hydroxy-3-methyl-butoxy)-6-trifluoromethyl-biphenyl-3-ylmethoxy]-pyridin-2-yl}-cyclopropanecarboxylicAcid

The title compound is prepared from(1S,2S)-2-[5-(3-bromo-4-trifluoromethyl-benzyloxy)-pyridin-2-yl]-cyclopropanecarboxylicacid ethyl ester and2-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-butan-2-olfollowing a procedure analogous to that described for Example 17; thecoupling reaction is conducted with 1 mol % Pd(OAc)₂ and 2 mol % SPhosat 110° C. for 2 h, and saponification is done with 0.5 mol/L KOH inethanol and tetrahydrofuran (1:1) at 50° C. LC (method 1): t_(R)=1.00min; Mass spectrum (ESI⁺): m/z=516 [M+H]⁺.

The invention claimed is:
 1. A compound of formula (I)

wherein R is selected from the group consisting of H, F, Cl, Br, I,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, NC—,HNR^(N)—C(═O)—, C₁₋₄-alkyl-NR^(N)—C(═O)—, C₃₋₆-cycloalkyl-NR^(N)—C(═O)—,heterocyclyl-NR^(N)—C(═O)—, heteroaryl-NR^(N)—C(═O)—, HOOC—,C₁₋₄-alkyl-O—C(═O)—, O₂N—, HR^(N)N—, C₁₋₄-alkyl-R^(N)N—,C₁₋₄-alkyl-C(═O)NR^(N)—, C₃₋₆-cycloalkyl-C(═O)NR^(N)—,heterocyclyl-C(═O)NR^(N)—, heteroaryl-C(═O)NR^(N)—,C₁₋₄-alkyl-S(═O)₂NR^(N)—, C₃₋₆-cycloalkyl-S(═O)₂NR^(N)—,heterocyclyl-S(═O)₂NR^(N)—, heteroaryl-S(═O)₂NR^(N)—, HO—,C₁₋₆-alkyl-O—, HOOC—C₁₋₃-alkyl-O—, C₃₋₆-cycloalkyl-C₁₋₃-alkyl-O—,heterocyclyl-C₁₋₃-alkyl-O—, phenyl-C₁₋₃-alkyl-O—, C₃₋₆-cycloalkyl-O—,heterocyclyl-O—, heteroaryl-O—, C₁₋₄-alkyl-S—, C₃₋₆-cycloalkyl-S—,heterocyclyl-S—, C₁₋₄-alkyl-S(=O)—, C₃₋₆-cycloalkyl-S(═O)—,heterocyclyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl-S(═O)₂—,heterocyclyl-S(═O)₂—, phenyl-S(═O)₂—, heteroaryl-S(═O)₂—,HNR^(N)—S(═O)₂—, C₁₋₄-alkyl-NR^(N)—S(═O)₂—, heterocyclyl, phenyl, andheteroaryl, wherein each alkyl, cycloalkyl, and heterocyclyl group orsub-group within the groups forming R is optionally substituted with 1or more F atoms and optionally substituted with 1 to 3 groupsindependently selected from Cl, C₁₋₃-alkyl, NC—, (R^(N))₂N—, HO—,C₁₋₃-alkyl-O—, and C₁₋₃-alkyl-S(═O)₂—; and wherein each phenyl andheteroaryl group or sub-group within the groups forming R is optionallysubstituted with 1 to 5 substituents independently selected from F, Cl,C₁₋₃-alkyl, HF₂C—, F₃C−, NC—, (R^(N))₂N—, HO—, C₁₋₃-alkyl-O—, F₃C—O—,and C₁₋₃-alkyl-S(═O)₂—; wherein each heterocyclyl group or sub-groupwithin the groups forming R is selected from a cyclobutyl group wherein1 CH₂ group is replaced by —NR^(N)— or —O—; a C₅₋₆-cycloalkyl groupwherein 1 CH₂ group is replaced by —C(═O)—, —NR^(N)—, —O—, —S— or—S(═O)₂— and/or 1 CH group is replaced by N; a C₅₋₆-cycloalkyl groupwherein 1 CH₂ group is replaced by —NR^(N)— or —O—, a second CH₂ groupis replaced by —NR^(N)—, —C(═O)— or —S(═O)₂— and/or 1 CH group isreplaced by N; and a C₅₋₆-cycloalkyl group wherein 2 CH₂ groups arereplaced by —NR^(N)— or 1 CH₂ group by —NR^(N)— and the other by —O— anda third CH₂ group is replaced by —C(═O)— or —S(═O)₂— and/or 1 CH groupis replaced by N; wherein each heteroaryl group or sub-group within thegroups forming R is selected from tetrazolyl and a 5- or 6-memberedheteroaromatic ring which contains 1, 2, or 3 heteroatoms independentlyof each other selected from ═N—, —NR^(N)—, —O—, and —S—, wherein inheteroaromatic groups containing a —HC═N— unit this group is optionallyreplaced by —NR^(N)—C(═O)—; wherein in heteroaryl and heterocyclyl ringswith one or more NH groups, each of said NH groups is replaced byNR^(N); R¹ is selected from the group consisting of H, F, Cl,C₁₋₄-alkyl, C₃₋₆-cycloalkyl-, HO—C₁₋₄-alkyl, C₁₋₄-alkyl-O—C₁₋₄-alkyl,NC—, HO—, C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—, C₁₋₄-alkyl-S—,C₁₋₄-alkyl-S(O)—, and C₁₋₄-alkyl-S(O)₂—, wherein any alkyl andcycloalkyl group or sub-group within the groups forming R¹ is optionallysubstituted with 1 or more F atoms, and wherein multiple R¹ may beidentical or different if m is 2, 3 or 4; m is an integer selected from1, 2, 3, and 4; R² is selected from the group consisting of H, F, Cl,C₁₋₄-alkyl, NC—, and C₁₋₄-alkyloxy, wherein any alkyl group or sub-groupwithin the groups forming R² is optionally substituted with 1 or more Fatoms, and wherein multiple R² may be identical or different if n is 2or 3; R³ is selected from the group consisting of H, F, Cl, C₁₋₄-alkyl,NC—, and C₁₋₄-alkyl-O—, wherein each alkyl group or sub-group within thegroups forming R³ is optionally substituted with 1 or more F atoms; n isan integer selected from 1, 2, and 3; R^(N) is independently of eachother selected from the group consisting of H, C₁₋₄-alkyl,HO—C₁₋₄-alkyl-(H₂C)—, C₁₋₃-alkyl-O—C₁₋₄-alkyl-, C₁₋₄-alkyl-C(═O)—,C₁₋₄-alkyl-NH—C(═O)—, C₁₋₄-alkyl-N(C₁₋₄-alkyl)-C(═O)—,C₁₋₄-alkyl-O—C(═O)—, and C₁₋₄-alkyl-S(═O)₂—, wherein each alkyl group orsub-group within the groups forming R^(N) is optionally substituted with1 or more F atoms; wherein in any definition mentioned hereinbefore, ifnot specified otherwise, any alkyl group or sub-group may bestraight-chained or branched, or a salt thereof.
 2. The compoundaccording to claim 1, wherein R is selected from the group consisting ofH, F, Cl, C₁₋₄-alkyl, NC—, H₂N—C(═O)—, HOOC—, H₂N—,C₁₋₃-alkyl-C(═O)NR^(N)—, C₁₋₄-alkyl-S(═O)₂NR^(N)—, HO—, C₁₋₅-alkyl-O—,HOOC—CH₂—O—, cyclopropyl-H₂C—O—, heterocyclyl-CH₂—O—, phenyl-CH₂—O—,C₃₋₆-cycloalkyl-O—, heterocyclyl-O—, heteroaryl-O—,heterocyclyl-S(═O)₂—, heterocyclyl, and heteroaryl, wherein each alkyl,cycloalkyl, and heterocyclyl group or sub-group within the groupsforming R is optionally substituted with 1 or more F atoms andoptionally substituted with 1 group selected from Cl, H₃C—, NC—,R^(N)HN—, HO—, H₃C—O—, and H₃C—S(═O)₂—; wherein each heteroaryl group orsub-group within the groups forming R is optionally substituted with 1to 2 substituents independently selected from F, Cl, H₃C—, F₃C—, NC—,(R^(N))₂N—, HO—, H₃C—O—, F₃C—O—, and H₃C—S(═O)₂—; wherein eachheterocyclyl or sub-group within the groups forming R is selected from acyclobutyl group wherein 1 CH₂ group is replaced by —NR^(N)— or —O—; aC₅₋₆-cycloalkyl group wherein 1 CH₂ group is replaced by —C(═O)—,—NR^(N)—, —O—, —S— or —S(═O)₂— and/or 1 CH group is replaced by N;wherein each heteroaryl group or sub-group within the groups forming Ris selected from tetrazolyl, a 5-membered heteroaromatic ring whichcontains 1, 2 or 3 heteroatoms independently of each other selected from═N—, —NH—, O and S, and a 6-membered heteroaromatic ring which contains1 or 2 ═N— atoms, wherein a —HC═N— unit is optionally replaced by—NH—C(═O)—; and wherein in each heteroaryl and heterocyclyl group orsub-group mentioned before containing one or more NH, said NH group(s)is/are replaced by NR^(N); or a salt thereof.
 3. The compound accordingto claim 1, wherein R is selected from the group consisting of H,C₁₋₃-alkyl, Cl, (H₃C)₂N—C(═O)—, HOOC—; H₃C—O— optionally monosubstitutedwith C₁₋₄-alkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl,wherein the C₁₋₄-alkyl group optionally attached to H₃C—O— is optionallymonosubstituted with HO— or H₃C—S(═O)₂—, and wherein said oxetanyl,tetrahydrofuranyl, and tetrahydropyranyl groups are optionallymonosubstituted with H₃C—; tetrahydrofuranyl-O— andtetrahydropyranyl-O—; and a heteroaryl group selected from pyrazolyl,tetrazolyl, pyridyl, pyridin-2-onyl, pyridazinyl, pyrazinyl, andpyrimidinyl, wherein each of said heteroaryl groups is optionallymonosubstituted with H₃C— or H₃C—O—, and wherein each H—N group in saidheteroaryl groups is optionally replaced with H₃C—N or(H₃C)₂C(OH)—H₂C—N; or a salt thereof.
 4. The compound according to claim1, wherein R¹ is H, F, Cl, H₃C—, H₃C—H₂C—, (H₃C)₂HC—, F₃C—, NC—, orH₃C—O—; m is 2; R² is H, F, or F₃C—; n is 1 or 2; and R³ is H; or a saltthereof.
 5. The compound according to claim 1, wherein R¹ is H or H₃C—;or a salt thereof.
 6. The compound according to claim 1, wherein R isselected from the group consisting of H, C₁₋₃-alkyl, Cl, (H₃C)₂N—C(═O)—,HOOC—; H₃C—O— optionally monosubstituted with C₁₋₄-alkyl, oxetanyl,tetrahydrofuranyl, or tetrahydropyranyl, wherein the C₁₋₄-alkyl groupoptionally attached to H₃C—O— is optionally monosubstituted with HO— orH₃C—S(═O)₂—, and wherein said oxetanyl, tetrahydrofuranyl, andtetrahydropyranyl groups are optionally monosubstituted with H₃C—;tetrahydrofuranyl-O— and tetrahydropyranyl-O—; and a heteroaryl groupselected from pyrazolyl, tetrazolyl, pyridyl, pyridin-2-onyl,pyridazinyl, pyrazinyl, and pyrimidinyl, wherein each of said heteroarylgroups is optionally monosubstituted with H₃C— or H₃C—O—, and whereineach H—N group in said heteroaryl groups is optionally replaced withH₃C—N or (H₃C)₂C(OH)—H₂C—N; R¹ is selected from the group consisting ofH, F, Cl, H₃C—, H₃C—H₂C₁₋₃, (H₃C)₂HC—, F₃C—, NC—, and H₃C—O—; m is 2; R²is H, F, or F₃C—; n is 1 or 2; and R³ is H; or a salt thereof.
 7. Thecompound according to claim 1, wherein R is selected from the groupconsisting of H, Cl, H₃C—H₂C—, (H₃C)₂N—C(═O)—, HOOC—, H₃C—O—,

wherein the asterisk (-*) indicates the site/point of attachment; R¹ isH or H₃C—; m is 2; R² is H, F, or F₃C—; n is 1 or 2; and R³ is H; or asalt thereof.
 8. The compound according to claim 1, with the structureand stereochemistry shown in formulae I.1, I.2, I.3, I.4, I.5, or I.6

or a salt thereof.
 9. A pharmaceutically acceptable salt of a compoundaccording to claim
 1. 10. A pharmaceutical composition comprising one ormore compounds according to claim 1 or one or more pharmaceuticallyacceptable salts thereof, optionally together with one or more inertcarriers and/or diluents.
 11. A method for treating a disease orcondition which can be influenced by the modulation of the function ofGPR40, comprising administering to a patient in need thereof apharmaceutically effective amount of a compound according to claim 1 ora pharmaceutically acceptable salt thereof, wherein the disease orcondition is selected from type 2 diabetes mellitus, insulin resistance,and obesity.
 12. A pharmaceutical composition comprising one or morecompounds according to claim 1 or one or more pharmaceuticallyacceptable salts thereof and one or more additional therapeutic agents,optionally together with one or more inert carriers and/or diluents. 13.The pharmaceutical composition according to claim 12 wherein one or moreadditional therapeutic agents is selected from the group consisting ofantidiabetic agents, agents for the treatment of overweight and/orobesity and agents for the treatment of high blood pressure, heartfailure and atherosclerosis.